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Panelists of Anti-TB Drugs and Arrhythmia: Theoretical Concern or Real Risk? and GHDonline staff

Anti-TB Drugs and Arrhythmia: Theoretical Concern or Real Risk?

Posted: 29 Jun, 2015   Recommendations: 19   Replies: 58

Enthusiasm for the new anti-tuberculosis drugs bedaquiline and delaminid is tempered by concerns about their potential to cause cardiotoxicity. The drugs are associated with QT prolongation—an abnormal pattern on the electrocardiogram that can lead to a fatal arrhythmia. Older agents like fluoroquinolones, clofazimine and thioridazine have also been noted to cause this abnormality. It is unclear, however, whether QT prolongation is a perfect proxy measure for the risk of sudden cardiac death due to arrhythmia and which patients with this abnormality are at the highest risk for an adverse outcome.

Bedaquiline and delamanid are likely to form the backbone of treatment for drug-resistant TB in some combination with other potentially cardiotoxic drugs despite these risks because the need for effective therapy is so great. As we develop and modify treatment regimens using combinations of these new and old drugs, we will need to accurately account for and manage the risk of drug-induced cardiotoxicity. This Expert Panel will explore the risk of QT prolongation in emerging drug-resistant tuberculosis (DR-TB) therapy.

We’re pleased to welcome the following panelists for this discussion:

• Dr. Mathilde Jachym – Pulmonologist, Centre Hospitalier de Bligny, France
• Dr. Gene Kwan – Cardiologist, Boston University Medical Center, USA; Health and Policy Advisor for Non-communicable Diseases, Partners In Health, USA
• Dr. Michael Rich – Global Health Physician, Brigham and Women’s Hospital, Partners In Health, USA
• Dr. Peter Zimetbaum – Associate Chief and Director of Clinical Cardiology, Beth Israel Deaconess Medical School, USA

During our week-long discussion, panelist will address the following questions:
• What is the risk of fatal cardiac arrhythmias in DR-TB treatment?
• What are the advantages and disadvantages of using QTc prolongation as the approximation of risk for arrhythmia in patients on DR-TB treatment?
• What are the obstacles to implementation of electrocardiogram monitoring and how can they be overcome?
• What is the best strategy for managing arrhythmia risk in patients on DR-TB treatment?
• How should cardiotoxic anti-TB drugs be combined into treatment regimens?

We encourage you to join the conversation and share your comments and questions with the community.

Replies

 

Sofia Alexandru Replied at 9:28 AM, 29 Jun 2015

Thank you so much for very interesting information!

I will participate with pleasure in discussion of this important topic

Best regards,
Sofia

Anita qaffari.MD Replied at 6:26 PM, 29 Jun 2015

hi
I.
Prolonged Q-T intervals may never cause any problems. However, physical or emotional stress may "trip up" a heart susceptible to prolonged Q-T intervals and cause the heart's rhythm to spin out of control, triggering life-threatening, irregular heart rhythms (arrhythmias) including:

Torsades de pointes — 'twists of the points.' This arrhythmia is characterized by your heart's two lower chambers (ventricles) beating fast, making the waves on an ECG monitor look twisted. When this arrhythmia occurs, less blood is pumped out from your heart. Less blood then reaches your brain, causing you to faint suddenly and, often, without any warning.

If a torsades de pointes episode is short — lasting less than one minute — your heart can correct itself seconds later, and you regain consciousness on your own. However, if a torsades de pointes episode persists, it can lead to a life-threatening arrhythmia called ventricular fibrillation.
Ventricular fibrillation. This condition causes the ventricles to beat so fast that your heart quivers and effectively ceases pumping blood. Unless your heart is shocked back into a normal rhythm by a device called a defibrillator, ventricular fibrillation can lead to brain damage and death. It's thought that long QT syndrome may explain some cases of sudden death in young people who otherwise appear healthy.

Dr Satish Kaipilyawar Replied at 1:40 AM, 30 Jun 2015

Thanks a lot, this is valuable information for me, I will surely participate.

Prof.Dr.Matiur Rahman Replied at 6:13 AM, 30 Jun 2015

Excellent discussion I am herewith sharing few papers regarding use of Bedaquilin inMDR TB which may be useful for those participating in this academic discussion.I will give my detailed input point by point later.

Attached resources:

egh Eduardo Gotuzzo Replied at 8:04 AM, 30 Jun 2015

I agree with the need to made evalaution becuase bedaquiline had
atransitory increase Qt
And moxi one of the best tbcmdr drug also produce this even more than
levofloxacin
Know we are doing a pharmakinetics with diffrent doses of levo and one of
the main objetive is reviewwith EKG these potentials chamge
Rememberthis one of the main reason why several floirquinoles was retired
of the market in the past
We need to have a close work with our cardiologists
Regards
E gotuzzo

Anita qaffari.MD Replied at 1:29 PM, 30 Jun 2015

Because treatment of drug resistant TB and use of second-line therapy is highly specialised, the Department, in consultation with the Tuberculosis Advisory Committee, has recommended that specific clinical criteria must be met in order to be eligible for Department of Health funding of second-line drugs. &MDR

just thinking about it,,,I am sure this is a matter of Customers’ satisfaction of drugs cost not quality  
.just my opinion!.
maybe it is a main responsibility  the doctors, nurses and patients, and families to use their right to be aware of this drug change
The effectiveness and safety of bedaquiline for the treatment of MDR TB have not been studied adequately in these populations that leads to Quality of evidence: low.

Expert opinion: The possible benefits of using bedaquiline outweigh the potential risk.
!!!!!
but again finding myself in a cul- de-sac 
,I am sure i have read in a article that  Janssen Therapeutics donated this drug to Resource limited countries ..

Asif Mahmud Replied at 2:04 AM, 1 Jul 2015

Look forward to a very valuable discussion.
Best regards
Asif

Anita qaffari.MD Replied at 5:52 AM, 4 Jul 2015

The use of bedaquiline with rifamycins or other drugs that induce or suppress CYP3A4 should be avoided, unless the anticipated benefits outweigh the risks associated with inadequate treatment of MDR TB; if bedaquiline is given with these drugs, monitoring of serum drug levels should be performed to ensure adequate therapy and minimize the risk for acquired drug resistance. Providers are encouraged to contact CDC for technical assistance and referral for monitoring serum drug levels if necessary.
Because bedaquiline has an extremely long terminal half-life (4–5 months), acquired resistance might occur when bedaquiline is the sole effective anti-TB drug in circulation. Prescribers should consider discontinuation of bedaquiline 4–5 months before scheduled termination of other drugs in the regimen to reduce or avoid an extended period of exposure to low levels of bedaquiline as a single drug.
Bedaquiline should be administered only by directly observed therapy (DOT) and with case management strategies. Such strategies might include the use of incentives and enablers (e.g., food certificates, bus passes, cash, or housing) to ensure adherence to the treatment regimen.
Patients should be advised that nonadherence to a treatment regimen could result in treatment failure, relapse, or acquired resistance. An evaluation for the development of resistance to the anti-TB regimen (including repeat drug susceptibility testing, if indicated) is recommended for patients with treatment failure or relapse.

Syed Rizwanuddin Ahmad Replied at 10:44 AM, 4 Jul 2015

Dear Dr. Dylan Tierney,

Thank you for organizing the expert panel on this very important and timely topic. I look forward to the discussion.

On a separate note, I have been inundated with multiple repeat messages from 2-3 folks since this am. Just wondering if this is only me or there is a system problem. Hopefully it can be fixed if its the latter.

Best wishes,

Syed Rizwanuddin Ahmad, MD, MPH, FISPE, FCP
Pharmacovigilance Consultant with a Special Interest to Strengthen National Medicines
Regulatory Authorities in Resource-limited countries
Ex-Consultant/Safety Reviewer, U.S. FDA (1998-2013)
Associate Professor (adjunct), Rutgers School of Public Health, NJ, USA
Assistant Professor (adjunct), Georgetown University School of Medicine, Washington, DC, USA
www.drugsafetyconsultant.com

Anita qaffari.MD Replied at 2:39 PM, 4 Jul 2015

Information on Bedaquiline donation

 

General

What is the Bedaquiline (BDQ) donation program?
 
On March 6, 2015, the United States Agency for International Development (USAID) and the Johnson & Johnson affiliate, Janssen Therapeutics, signed an agreement to provide Bedaquiline free to eligible MDR-TB patients, according to WHO interim recommendations on the use of the drug.
 
Under the agreement, Janssen will donate $30 million worth (30,000 treatment courses) of the drug SIRTURO® (bedaquiline) over a 4 year period to be used for the treatment of drug-resistant TB. The drug donation will enable over 100 low- and middle-income eligible countries to access the life-saving drug for free within their existing MDR-TB programs. The donation will be provided through USAID’s agreement with the Stop TB Partnership’s Global Drug Facility to facilitate access to quality-assured medicines.
 
Why Bedaquiline?
According to the WHO’s Global TB Report 2014, an estimated 480 000 people developed MDR-TB in 2013 and 210 000 people died. Only one in four are diagnosed, and only one in five are put on treatment. Of this, less than half are successfully treated.
 
Left untreated, a single person with MDR-TB may infect 10-15 people every year. Antibacterial resistance to anti-tuberculosis drugs is a major public health problem that arises as a result of improper use of antibiotics and poor patient adherence to a long, often toxic, therapy.
The world needs new solutions for treating MDR-TB patients.  Bedaquiline is the first new class of antibiotics that has been FDA approved in over 50 years.  The use of this drug in combination with existing drugs could provide new hope for MDR-TB patients with very few treatment options.  The World Health Organization has issued interim recommendations on the use of Bedaquiline and has provided guidance to countries on its use.
 
How does the availability of this donation relate to WHO Interim Policy Guidance?
The WHO Interim Policy Guidance on BDQ: http://www.who.int/mediacentre/news/notes/2013/bedaquiline_mdr_tb_20130613/en/
issued in 2013 specifies that BDQ may be used as part of an MDR-TB treatment regimen for specific subgroups of MDR-TB patients and provided the following five conditions are met, as specified in the WHO Interim Policy Guidance on Bedaquiline: http://apps.who.int/iris/bitstream/10665/84879/1/9789241505482_eng.pdf
Eligibility

Is my country eligible for the Bedaquiline (BDQ) donation program?
Most countries that are eligible to request tuberculosis (TB) funding through the Global Fund (GF) are eligible to receive drugs through the bedaquiline donation program.  The Global Fund 2015 eligibility list is available here.  Some of the details are still being worked out on selected countries.
If using domestic budget, countries shall approach GDF for additional details.
 
What are the requirements countries must meet to qualify?
Countries must declare that they are able to meet all five of the conditions as per the WHO Interim Policy Guidance on BDQ. http://apps.who.int/iris/bitstream/10665/84879/1/9789241505482_eng.pdf

Anita qaffari.MD Replied at 3:40 PM, 4 Jul 2015

Measurement of the QT interval. QT prolongation can result in ventricular arrhythmias (torsades de pointes) and sudden death, and it is imperative that ECGs are used to monitor the QT interval regularly during bedaquiline use. The QT interval must be corrected for the heart rate and the adjusted value is referred to as the “QT-corrected” (QTc). The Fredericia correction method (QTcF) is preferred.
 A QTcF greater than 440 ms is considered prolonged.
 A QTcFvalue greater than 480 ms (or an increase of greater than 60 ms from baseline)
requires electrolyte testing and more frequent ECG monitoring.
 A QTcF interval of more than 500 ms is considered dangerous and discontinuing QT
prolonging drugs is indicated.
Low or high serum electrolyte concentrations in the presence of a QT-interval prolongation predisposes to arrhythmias.
Liver function monitoring. Because a higher incidence of liver toxicity was seen in the clinical arm of patients on bedaquiline, liver enzymes should be monitored monthly. If aminotransferase elevations are accompanied by total bilirubin elevation of more than twice the upper limit of normal, or aminotransferase elevations are more than five times the upper limit of normal, bedaquiline needs to be discontinued.

Marie Connelly Replied at 8:39 PM, 4 Jul 2015

My sincere apologies to our members and panelists for the many automated messages that were posted to this Expert Panel over the past day. While I'm afraid we can't unsend the emails you've received, we have removed these off-topic posts from the Expert Panel, and are working to ensure there won't be future messages of this nature.

We're looking for a rich discussion when the Expert Panel begins on Monday, but if you have any questions or concerns in the meantime, please don't hesitate to contact us directly: http://www.ghdonline.org/contact/

Marie Connelly
Manager of Community Strategy, GHDonline

Dylan Tierney Replied at 3:49 PM, 6 Jul 2015

Welcome to the GHDonline expert panel on anti-TB drugs and arrhythmia, running from July 6 to July 10.

We’ll be discussing various aspects of the topic, starting today with an examination of the risk of fatal cardiac arrhythmias in DR-TB treatment.

Please feel free to comment or ask questions of our panelists.

Mathilde Jachym Replied at 4:25 PM, 6 Jul 2015

Bedaquiline belongs to a new class of antituberculosis drug and has been approved by the US Food and Drug administration and the European Medicine Agency for the treatment of XMDR TB. The promising results of the first studies are counterbalanced by a worrying imbalance in the number of deaths found in the group treated by Bedaquiline versus the control group.
Bedaquiline is known to increase Qtc that may have a “torsade de pointe” as a consequence.
Among our 35 first patient treated in France, Bligny hospital, by Bedaquiline, 7 (20%) had an increase Qtc>= 60s from baseline and 3 (9%) had a Qtc value > 500ms. Bedaquiline was discontinued in the 2 patients due to persistent Qtc prolongation. One was receiving Moxifloxacine at that time and the other Clofazimine and Amiodarone. This last patient died Four month later due to malignancy : he had and advanced pharyngo-laryngeal cancer known before the start of the antituberculosis treatment.
No cardiac arrhythmia was recorded
(Guglielmetti CID 2015)
Trying to avoid drugs that have a similar effect on QTc is difficult because of the number of drugs involved : Moxifloxacine, Clofazimine, Delamanide, Methadone, Odansetron, Metoclopramide, Domperidone, Antiarythmics, Neuroleptics, Atazanavir, Darunavir, Lopinavir, Halofantrine, Mefloquine, Quinin, Fluconazole, Voriconazole, Citalopram, Salbutamol, Ondansetron...
In case of using two or more drug increasing the Qtc, we have a weekly control of ECG.

Gene Kwan Replied at 4:27 PM, 6 Jul 2015

Greetings to everyone. I’m excited to be here among our esteemed co-panelists. I am a cardiologist and global health researcher with a focus on the epidemiology and management of cardiovascular diseases in rural low-income countries — specifically Haiti and Rwanda. I am particularly interested in developing context-specific local guidelines and treatment protocols, as well as in the use of point-of-care diagnostic tests for heart disease. In addition, I am also interested in implementing resource-efficient care delivery strategies. While most of my work has involved portable echocardiography, I have also taught the clinical use of ECG. I hope to be able to speak specifically regarding the challenges and opportunities around QTc monitoring in the types of resource-limited settings where many patients with DR-TB live.

Gene Kwan Replied at 4:31 PM, 6 Jul 2015

What is the risk of fatal cardiac arrhythmias in DR-TB treatment?

To my knowledge, the specific risk is not precisely known but is may be low with QTc monitoring protocols. Our main metric for arrhythmia risk has been the length of the QTc. We do know that longer QTc carries with it a higher risk of arrhythmia - particularly Torsades de Pointes, a potentially fatal ventricular arrhythmia. Torsades risk rises with longer QTc (either acquired or congenital), and can result from electrolyte abnormalities, congenital genetic disorders of electrolyte channels, and the effect of certain medications. Thus, our worry about cardiac arrhythmias in DR-TB treatment stems from the observation that many of the drugs cause QTc prolongation.

Briefly (because I know we will discuss this in more detail later), there have been no clinically significant arrhythmias in the trials testing the new agents Bedaqueline and Delaminid. In the main safety and efficacy trial of Delaminid (NEJM 2012;366(23)) out of 321 patients given Delaminid, none manifested an arrhythmia or syncope. However, more patients noted palpitations than in the placebo group. In the trial, there was close monitoring of the QTc in the trial with a pre-defined protocol in the event of QT prolongation. Thus, as used and monitored in the clinical trial, Delaminid is safe from an arrhythmia perspective.

In smaller studies of Bedaqueline, including a real-world series of patients in whom Bdq was used compassionately, QT prolongation was noted but no significant arrhythmia occurred. (Guglielmetti, CID, 2014)

However, In a randomised, placebo-controlled trial, ten of 79 patients in the bedaquiline-containing group died (13%) versus two of 81 patients in the placebo group (2%). The increased deaths in the Bdq group occurred after the cessation of Bdq. Given the long half-life of Bdq, it is possible that Bdq toxicity may have contributed.

Overall, the medications bedaqueline and delaminid, when used in close ECG monitoring and clear protocols to decrease the risk of arrhythmias, are safe. The difficult part will be in ensuring monitoring systems are in place and functioning.

Dylan Tierney Replied at 10:55 PM, 6 Jul 2015

So would panelists categorize the risk of fatal cardiac arrhythmia in DR-TB treatment as “low but manageable”?

Or would you use more conservative terminology and, if so, why?

Tom Yates Replied at 1:45 AM, 7 Jul 2015

I understand the excess deaths in the BDQ phase 2 study were attributed to
progression of TB disease. I would be interested in how confident people
think we can be regards attribution of cause of death here? I suppose a
slow decline suggests progression of TB rather than an arrhythmia as the
underlying cause, although presumably one cannot exclude the possibility
that the terminal event was an arrhythmia if the patient was not monitored
at the time of death.

Michael Rich, MD MPH Replied at 3:23 AM, 7 Jul 2015

Greetings to all. I am a "TB doctor" working in Global Health and MDR-TB programs for 16 years. It is not often we get two cardiologists on a Panel with some TB specialists and Global Health doctors - I greatly look forward to the discussion. Thanks to all for the comments so far.

I would like to kick off discussion with a few questions to the cardiologists and pulmonologist on the panel. I think many have similar questions:

1) If a patient is clinically responding to a regimen that includes bedaquiline or delamanid at month 6 with no significant QT prolongation and the the Bdq or Dlm is deemed essential in the regimen (without it the patient would likely be on less than three effective anit-TB drugs), is there a significant cardiac risk for prolonging treatment past 6 months?

2) What do you recommend General Physicians and TB Doctors examine on the ECG? Just QT interval, rate, and rhythm?

3) For screening can we just let the ECG machine read the QT interval, rate and rhythm? Are there machines that are more accurate than others (and if so do you recommend any type of machines in particular)?

4) If screening with the ECG machine is allowed, can you suggest cut offs for which the patient should be referred for further testing and review by cardiologists or hospitalization?

5) Can you comment is a QT interval increase of 60 ms from baseline carry the same risks as going above the interval of 500 ms? Do medicines always need to be adjusted if QT interval is 60 ms above baseline, especially if the QT interval remains in a normal range?

Thanks, and I look forward to a discussion on these practical points that come up when I am disucussing cases with TB doctors.

Michael Rich

Gene Kwan Replied at 7:49 AM, 7 Jul 2015

Thanks to Tom and Michael for your questions.

I'll first start by briefly reviewing what is the QT interval and how it is measured.

The QT interval of the ECG represents the repolarization of the membrane of cardiac myocytes. Many ion channels work together to regulate repolarization. One of the primary channels i the IKr channel which regulates the charge across the membrane. Medications which impair the IKr channel (such as bedaqueline, delaminid, and a long list of other medicines) result in slower repolarization. The slower repolarization (and the prolonging of the QT interval which comes with it) is not, in it of itself, bad. What is bad is that minor ion fluxes can cause the membrane to depolarize before it is fully repolarized (called early after depolarizations - EADs). EADs are more likely to happen when repolarization is slower (and the QT is longer). EADs can lead to dangerous heart rhythm disturbances such as ventricular tachycardia and Torsades de Pointes (a specific type of ventricular tachycardia). Thus, the longer is the QT interval, the higher the risk of EADs and adverse heart rhythms.

Measuring the QT interval sounds straight forward. However, nature has a way of making things a bit more complicated. It turns out that the heart’s electrical system evolved to adjust to different heart rates. When the heart rate is fast, the repolarization has to happen quickly (in a shorter time period) to allow the heart to be ready for the next beat. Thus, the QT interval naturally becomes shorter as the heart rate increases (and the QT interval becomes longer at slower heart rates). Because of this, one must “correct” the QT interval for the heart rate.

The difficulty lies in the methods of correction. Some of the main correction methods are here:
Bazett: QTc = QT * RR^1/2
Fridericia: QTc = QT * RR^1/3
Framingham: QTc = QT + 0.154*(1000 – RR)

Bazett’s correction has been around the longest (since 1920) and has, by virtue of longevity, been given prominence in medical training. However, it was developed using only 39 healthy people at rest and does not perform as well as some other correction methods - particularly at the extremes of heart rates. The Fridericia and Framingham correction methods are more accurate when tested across larger populations with different heart rates and with medication-induced tachycardia, but are not as widely known.

There are also intricacies around measurement: In which lead to measure? Some advocateed for (a) using lead II for standardization, (b) the lead in which the T wave is best seen, (c) leads V2 or V3 which may be longer, or (d) leads V5 or V6 because the Q wave and T wave may be clearest. What if the QRS duration is long (meaning depolarization is slow). We would then expect the QT to be prolonged. Should we measure the JT interval instead?

All of this being said, there are good data showing an increased risk of arrhythmias with longer QTc (by any correction method). While using QTc may not be perfect, it has a good track record.

Samahel Joseph Replied at 1:09 PM, 7 Jul 2015

Hi Gene,
Thank you for the light you bring in this. This Cardio for everyone!!!
This is wonderful.

Samahel

Mathilde Jachym Replied at 5:25 PM, 7 Jul 2015

"How should cardiotoxic anti-TB drugs be combined into treatment regimens?"

We try to avoid to combine cardiotoxic anti TB drugs. Some time there is no option because of the number of resistance on DST.
The strategy is to have always 3 or 4 effective drugs
Use Levofloxacine instead of Moxifloxacine.
In some case, I introduced first BDQ and, after checking the absence of effect on the Qtc, I considered the introduction of clofazimine.

"If a patient is clinically responding to a regimen that includes bedaquiline or delamanid at month 6 with no significant QT prolongation and the the Bdq or Dlm is deemed essential in the regimen (without it the patient would likely be on less than three effective anit-TB drugs), is there a significant cardiac risk for prolonging treatment past 6 months?"

There is no data from the industry about treatment longer than 6 month, no data on the toxicity. We can just speak about the long half life of the Bedaquiline (BDQ) and about the risk of phospholopidosis induced by BDQ. Phospholipidosis is a lysosomial storage disorder characterized by the excess accumulation of phospholopids in tissues. Drug induced phopholipidosis are associated with clinical side effects like drug induced QT prolongation, myopathy, hepatotoxicity... There is no effective biomarker to predict the risk.
In the other hand XDR TB is a well known risk of death and failure to current treatment occurs in more than 60% cases. And we have data on the risk of failure when there is treatment too weak or too short.
My colleagues from "Doctors without border" experienced patients who relapsed after the discontinuation of BDQ (stopped after 6 month)

The treatment must be restricted to the patients with a very bad prognostic but for these patients, consider a compassionate use of BDQ or Delamanid (Dlm) for more than 6 month may be the unique way to increase their chance of survival.
If, without BDQ or Dlm, threre is less than 3 effective drugs in the protocol the risk of cardiac side effect may be lowest than the risk of TB totally resistant.
We have some patients who experienced one year of treatment with BDQ in France without cardiac toxicity.
However, we must move forward very carrefully on this subject and take time to watch their evolution without jumping to conclusions


In our every day practice, When Qtc exceed 500ms
1 we control ECG 15 min later to be sure that the Qtc prolongation was not anomalous
2 we control potassium, calcium and magnesium levels
3 we try to avoid ancillary drugs witch may have an impact on the Qtc
4 we consider the other anti TB drugs that may have an impact on the QT

If we have to stop BDQ, and the Qtc return to baseline, we consider to re-challenge BDQ once all other potential Qtc conditions have been addressed.
(Harausz Int J Tuberc Lund Dis 19(4):385-391)

Dylan Tierney Replied at 11:37 PM, 7 Jul 2015

Posted on behalf of Peter Zimetbaum

1) If a patient is clinically responding to a regimen that includes bedaquiline or delamanid at month 6 with no significant QT prolongation and the the Bdq or Dlm is deemed essential in the regimen (without it the patient would likely be on less than three effective anit-TB drugs), is there a significant cardiac risk for prolonging treatment past 6 months?

From the perspective of qt prolongation one would expect to see a problem early if it is going to occur. Attention to electrolyte depletion (potassium and magnesium) remains important.

2) What do you recommend General Physicians and TB Doctors examine on the ECG? Just QT interval, rate, and rhythm?

QT interval is the key concern but rhythm and rate should not be ignored.

3) For screening can we just let the ECG machine read the QT interval, rate and rhythm? Are there machines that are more accurate than others (and if so do you recommend any type of machines in particular)?

The machine read QT interval (regardless of the manufacturer) is helpful but not perfect. Rate and rhythm are also reasonably well characterized by most machines but physician inspection remains the gold standard.

4) If screening with the ECG machine is allowed, can you suggest cut offs for which the patient should be referred for further testing and review by cardiologists or hospitalization?

If the read is >500msec would make sure the ECG is over read.

5) Can you comment is a QT interval increase of 60 ms from baseline carry the same risks as going above the interval of 500 ms? Do medicines always need to be adjusted if QT interval is 60 ms above baseline, especially if the QT interval remains in a normal range?

These numbers are somewhat arbitrary but represent a reasonable level of concern. Increase by 60 ms is significant and should be a reason to hold medication or at least decrease the dose. This relative increase is important even if it reaches the upper limit of normal.

Dylan Tierney Replied at 11:47 PM, 7 Jul 2015

The QT prolongation, as Gene Kwan nicely explained, is a basically a marker for the risk of cardiac arrhythmia.

I'm curious to know, however, whether all QT prolongation should be regarded as carrying the same risk of arrhythmia. For instance, is 60ms of prolongation due to moxifloxacin to same as 60ms of prolongation due to bedaquiline in terms of risk for arrhythmia?

Gene Kwan Replied at 8:18 AM, 8 Jul 2015

Its great to have such a rich discussion. Today, I'll start by exploring today's topic: "What are the obstacles to implementation of electrocardiogram monitoring and how can they be overcome?"

CHALLENGES: In my mind, I feel there are 3 main obstacles in implementing a diagnostic monitoring strategy. I’ll review them here and discuss some innovations that may help:
1. Availability of ECG machines
2. Training for ECG interpretation
3. Systems to adequately track patients and identify those at high risk.

1. Availability of ECG machines: There are a lot of issues related to the availability of diagnostic tests, particularly in Low- and Middle-income countries. I’ll summarize some of them here:
• Cost of ECG machines and cost/supply of consumables. Some ECG machines can cost several thousands of dollars, which may be out of the budget of many health systems. In my experience, a lot of the ECG machines in low-income settings are generally donated machines which are about 15+ years old. On some levels, this is understandable — donated machines are “free” at first. However, even after purchasing or getting a donated machine, there is the ongoing costs of the necessary consumables such as thermal paper, gel electrodes or suction cups. There must also be a robust supply chain to ensure that the consumables are in adequate supply at the point of care.
• Robustness of ECG machines. As I mentioned, many of the machines may be old by the time they reach their field site. Also, machines, which may be designed to be on a high quality cart and rolled from point-to-point within a hospital with smooth floors, but not hold up to the bumps and vibrations of being rolled between hospital wards. Electrical cords can become frayed and non-functioning. Unstable electricity supplies may not be sufficient to power the devices, or, even worse, may have irregular voltage that can irreversibly damage the internal DC converters.
• National systems for procurement and/or donation of ECG machines. Having a national-level system for procurement has several advantages. Machines and consumables can be purchased in bulk, leading to possibly more favorable pricing on the international market. However, strong centralized procurement systems are needed to facilitate this. A survey by the WHO evaluated the presence of national systems and lists suggesting the basic package of medical devices at different levels of the health system, and the presence of a dedicated unit in MOH for handling health technology (http://www.who.int/gho/health_technologies/medical_devices/en/). 41% of 155 countries do not have national standards or recommended lists of medical devices for different types of healthcare facilities or specific procedures. You can search this map (http://gamapserver.who.int/mapLibrary/app/searchResults.aspx) to see if your country has a national list.

2. Training in the interpretation of ECGs.
• As Peter mentioned, the on-board computerized algorithms for reading the QT interval are not perfect - though they may be close. The ECG should always be manually reviewed to measure the QT interval directly. This gets into some of the challenges I previously mentioned: Which leads to use? How to account for baseline wide QRS? It may also be difficult to know which QT correction formula is used by the computer.
• In practice, I generally measure the QT myself in several leads. If my directly measured QT matches the QT noted by the computer, I generally assume that the QTc formula is accurate. However, if my measured QT is different than the computer generated QT, I recalculate the QTc manually.

3. Systems to adequately track patients and identify those at high risk.
• Perhaps the most challenging part is the development of chronic care delivery systems. Many health care systems in low-income countries were established to care for acute conditions — diarrhea, fever, pneumonia, etc. They were not necessarily designed for chronic disease management. Usable and simple methods for information management are needed — whether they be paper-based registries or more sophisticated electronic systems. Whatever is used, the information system must be able to record patient contact information and some data regarding the medical condition.

INNOVATIONS: There are solutions to many of these challenges.
• Lower cost ECG machines have been developed. One example is a machine developed by GE Healthcare in India (http://www3.gehealthcare.in/en/Products/Categories/Diagnostic_ECG/Resting/MAC_i). They worked with local doctors to make a context-appropriate device specific for India. It is fast charging, has a long battery life, is robust, and portable. It sells for around $500 per unit. I can’t speak specifically to the QT measuring capability of the machine, but its probably good enough for manual reading, at least. There are also ECG devices that work through a standard laptop (with electrodes the connect via a USB port). Also, more and more mobile phone peripherals for ECG analysis are being developed. While a majority of these use only a few leads (and not all standard 12 leads), it is only a matter of time until a high-quality 12-lead ECG device can fit in your pocket.
• ECG with a digital display function. Many ECG machines have electronic displays in which either no paper is needed, or the display can be used as a backup in case there is no paper. While reading the QT on a screen may be difficult, it is better than nothing if there is a stock-out of paper!
• Tele-medicine and remote reading. Many countries have invested in tele-health technologies for ECG remote reading — particularly Brazil and India (http://www.who.int/medical_devices/innovation/compendium_med_dev2012_9.pdf). While most of the applications are for the interpretation of acute myocardial ischemia, similar systems can be used for QTc verification by experts.
• Web-based learning. Learning to measure the QT interval is not particularly difficult. Online-based courses and worksheets can be developed to facilitate learning, measure competency, and standardize methods across providers. Continued monitoring and evaluation systems are needed to ensure that providers continue to measure and correct the QT appropriately.
• Chronic care systems: For the past 20 years, the HIV-AIDS and TB epidemics have led to an influx in investment for chronic disease systems. For DR-TB, registers and data collection tools need to begin to incorporate QTc data. While this may sound simple, it may be more difficult in practice. Having a field for QTc at each visit may serve as a reminder to check the ECG and compare the QTc to a prior one.

I hope that my thoughts are helpful for the discussion. I’d love to hear comments from others in the field who also have struggled with these issues.

Dylan Tierney Replied at 9:50 AM, 8 Jul 2015

Posted on behalf of Peter Zimetbaum (edited for clarity)

I'm curious to know, however, whether all QT prolongation should be regarded as carrying the same risk of arrhythmia. For instance, is 60ms of prolongation due to moxifloxacin to same as 60ms of prolongation due to bedaquiline in terms of risk for arrhythmia?

The risk of arrhythmia is not always the same. For example, QT prolongation with amiodarone wouldn't be that concerning because the multi-channel blocking properties of the drug may protect from torsades de pointes.

Most drugs, however, don't have this feature so I would consider the risk of anti-TB drugs generally similar. I would have to assume that the same concern for QT prolongation with moxifloxacin would apply w bedaquiline.

Dylan Tierney Replied at 10:23 AM, 8 Jul 2015

The need for QT monitoring in the treatment of DR-TB may not be critical at this exact moment in time but it will surely grow as new drugs like bedaquiline and delaminid become available. So it will be increasingly important to figure out how to implement high quality ECG monitoring in places that are treating patients with DR-TB.

I was excited to read Gene Kwan’s commentary on the state of ECG monitoring in resource limited settings and his ideas for innovative approaches to improving access to this vital technology. I’m concerned, though, that there isn’t enough awareness around the risk of QT prolongation and cardiac arrhythmia to generate enough political will to make the necessary investments in new technology.

What do community members think? Should developing ECG monitoring capabilities be a priority for NTP programs? Where does this need sit in the long list of needs for DR-TB care in resource-limited settings? Where should it sit? At the top? In the middle? Or more towards the bottom?

Lorenzo Guglielmetti Replied at 4:14 PM, 8 Jul 2015

Thanks to all of you for this very enriching discussion.

I have a couple of questions, mainly for our Cardiologists (such a rare opportunity to have them in the panel):
- Which are the clinical risk factors for developing prolonged QTc interval and consequent arrhytmias?
- Are there any genetic factors playing a role in the development of arrhytmias, which could eventually be used to identify groups at high risk?

Ancha Pele Replied at 1:19 AM, 9 Jul 2015

The discussion is very interesting. Actually is complicated, should be avaluated the risks and benefits of the use of these new drogs and criate condicions to develop ECG monitoting capabilities for all physician...

Gene Kwan Replied at 1:35 AM, 9 Jul 2015

Thank you for the comments. Dr. Guglielmetti - it is an honor to have the author of one of the studies we previously cited in the "audience."

Q: Which are the clinical risk factors for developing prolonged QTc interval and consequent arrhytmias?
A: The main ones are electrolyte abnormalities - particularly hypokalemia, hypomagnesemia, and hypocalcemia. Thus, patients taking diuretics should have their electrolytes closely monitored when also receiving medicines that prolong the QT. Bradycardia can also increase the risk of drug-induced QT prolongation. While heart failure and left ventricle hypertrophy are associated with ventricular tachycardias, they are usually not in the setting of longer QT. Often with acute stroke, the QT will be prolonged. In the rare case that a patient treated with bedaqueline or delaminid has an acute stroke, vigilant QT monitoring should be performed.

Q: Are there any genetic factors playing a role in the development of arrhytmias, which could eventually be used to identify groups at high risk?
A: The main genetic factors are in patients with congenital channelopathies - congenital genetic abnormalities of the ion channels which regulate the myocardial membrane potential. In general, they are identified as congenital Long QT Syndromes (LQTS). There are various types caused by different underlying genetic disorders. Overall, not surprisingly, they share the similar phenotype of prolonged QT on ECG. Taking QT-prolonging medicines on top of a background of a congenital LQTS raises the risk for arrhythmia even higher. Genetic testing is very expensive and takes a long time. Evaluating for such conditions by baseline ECG is sufficient.

Please keep the questions coming!

adam abass Replied at 5:53 AM, 9 Jul 2015

So delighted to be part of this noble family.Hope to give off my best

Peter Cegielski Replied at 10:25 AM, 9 Jul 2015

Very interesting discussion! Thank you to everyone participating, asking and answering these enlightening and important questions. My question has to do with concurrent use of a drug like verapamil that is sometimes used for cardiac arrhythmias. Verapamil (and other ion channel blockers) has an interesting theoretical potential benefit in that it blocks some of the membrane-associated mycobacterial efflux pumps that pump out anti-TB drugs, making them less effective and leading to drug resistance. Thanks again.

Peter Cegielski Replied at 10:48 AM, 9 Jul 2015

Just to clarify, I meant the mycobacterial efflux pumps can make some of the anti-TB drugs less effective (by lowering their intracellular concentration) and may lead to drug resistance. Blocking the efflux pumps would make the anti-TB drugs more effective and may prevent drug resistance. Again, this is hypothetical.

Dylan Tierney Replied at 12:45 PM, 9 Jul 2015

Consider the hypothetical patient with newly diagnosed, smear positive preXDR-TB (resistant to kanamycin). The treatment regimen is linezolid, clofazimine, bedaquiline, capreomycin, moxifloxacin, and pyrazinamide. Let’s say QTc is 510ms after month one of therapy, up from 440ms at baseline. The patient remains smear positive.

From the comments previous posted by Mathilde and Gene, first step in management would be to make sure potassium and magnesium are replete. If QT continues to be prolonged, it seems like stopping one of the QT prolonging medications would have to be considered. But I’m wondering if there are any circumstances when it would be okay to continue therapy with stable prolonged QT. Put simply, how do we choose between the risk of cardiac arrhythmia and the risk of undertreating the tuberculosis disease?

Not to be impertinent, but would an implantable cardioverter defibrillator ever be practical in a situation where the goal was to maximize the efficacy of anti-TB therapy over risk of cardiac arrhythmia?

Gene Kwan Replied at 1:18 PM, 9 Jul 2015

Regarding Peter Cegielski's comments on verapamil blockade of the mycobacterial efflux pumps:
- This is an interesting theoretical interaction. On one hand, using verapamil may increase the intracellular concentration of the anti-mycobacterial medications, potentially making the therapy more effective.
- On the other hand, blocking the efflux pumps may also increase the likelihood of toxicity (and possibly QT prolongation) from the medications.
- I don't think we have the answer right now (more research needed), but dose-adjusting may be needed in cases where drug-drug interactions affect the pharmacokinetics and pharmacodynamics.

Michael Rich, MD MPH Replied at 2:46 PM, 9 Jul 2015

Dear all,
Thanks for the prompt and insightful answers from the cardiologists and the discussion from the participants.

WHO’s Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-resistant Tuberculosis, 2015 provides a nice review on the frequency of QT interval monitoring and management of QT prolongation for bedaquiline (Box A4.1.3, page 354) and delamanid (Box A4.2.2, 384). I recommend these sections to all.

One issue that I have noticed in the WHO Companion handbook is that “K+, Mg++ and ionized Ca++ should be monitored monthly while on bedaquiline and delamanid. This makes medical sense as the anti-TB Group 2 injectable agents cause electrolyte wasting which can potentiate an arrhythmia with QT prolongation. However, most MDR-TB programs have been monitoring only for potassium and if found to be low then check other electrolytes.

I would like to know the opinion of the cardiologists on how important it is to screen monthly for all three electrolytes (K+, Mg++ and ionized Ca++) versus screening monthly for K+ only and then checking other electrolytes when K+ is low? Please consider screening monthly for all three electrolytes is a significant hardship for most programs.

A second question, given the strong potential of the injectable agents to result in electrolyte wasting and hypokalemia, is there benefit in giving a small daily supplement of potassium, magnesium and calcium? As a clinician treating MDR-TB patients, I have never seen a patient while on the injectable agent and a supplement end up having a high serum level of K+ or Mg++. I feel there is little danger in hyperkalemia or hypermagnesium while on the injectable agent. There could be benefit in staying “ahead of the game” in terms of serum electrolytes while on QT prolonging drugs and electrolyte wasting agents. (Please note to all readers that supplements that are positive ions should be dosed apart from the fluoroquinolones as decrease absorption of the fluoroquinolones can result when taken together).

A third request for the cardiologists, can you give us some findings on ECG in respect to the new TB drugs that you would lead you to immediate hospitalization with continuous heart monitoring. I think most programs will hospitalize for QT intervals above 500 ms, but is this always necessary?

Thank you,
Michael

Mathilde Jachym Replied at 4:58 PM, 9 Jul 2015

Thank you Michael Rich for your comment.
I'm not sure a small daily supplementation of K+ or Ca++ would be a good idea without checking the serum levels.
Linezolid is known to provide hyper kaliemia and I have 2 patient without renal impairment or adrenal insufficiency who experienced hyper kaliemia. The level was moderate and without ECG consequence but I wonder what would have happen if they have had systematic supplementation.
TB is a granulomatous illness and hypercalcemia is not unusual. In addiction, our patient are very often bedridden at the beginning of the treatment and severe hypercalcemia may occur at that time.
I have a more nuanced opinion about Mg++ for I have never seen hyper magnesemia

Dylan Tierney patient has a QTc>500ms. I would stop clofazime and bedaquiline. I presume there is no alternative drug regarding to the results of DST except perhaps Clavulanique Acid+ Imipen or Meropenem. I would add this association till the normalisation of the QTc. Then try to reintroduce BDQ.
In my practice of this strategy, the QTc is quite varying, one day above 500ms and the day after a little under 500. Therefore, it's difficult to find the good time to re-introduce BDQ.
May I ask the cardiologist if a 24h recording ECG (holter) is more accurate to detect the risk of evens "Early After Depolarization (cf Gene Kwan comment) than the QTc value ?

Syed Rizwanuddin Ahmad Replied at 8:08 PM, 9 Jul 2015

Dear All,

Thank you to the expert panel for their useful contribution on this hot
topic. Thank you also to Drs. Tierney and Rich for some practical questions
that practitioners face in real life. This is a great start and good
refresher for anyone interested in anti-TB drugs associated QT
prolongation.

I am very much interested to know in which countries these drugs have been
introduced so far? Are there any pharmacovigilance system in place in these
countries to monitor the safe use of these products? Are folks in these
countries adequately trained to monitor the safety of these products? I am
afraid that if there is no system in place, we will not be able to fully
understand the safety profile of these drugs in a timely fashion. We
already know that resource-limited settings have special situations and may
be lacking on functional EKG machines; trained professionals to read and
interpret the EKG findings; and we know that the data around QT are of
varying quality and EKGs are often not available when one would like to see
them.

Thank you again,

Best wishes,

Rizwan

Syed Rizwanuddin Ahmad, MD, MPH, FISPE, FCP
Pharmacovigilance Consultant with a Special Interest to Strengthen
National Medicines Regulatory Authorities in Resource-limited settings
Ex-Consultant/Safety Reviewer, U.S. FDA (1998-2013)
Associate Professor (adjunct), Rutgers School of Public Health, NJ, USA
Assistant Professor (adjunct), Georgetown University School of Medicine,
Washington, DC, USA
www.drugsafetyconsultant.com

Gene Kwan Replied at 12:22 AM, 10 Jul 2015

Thanks for the great questions and comments. I'll answer some here.

Q: May I ask the cardiologist if a 24h recording ECG (holter) is more accurate to detect the risk of evens "Early After Depolarization (cf Gene Kwan comment) than the QTc value ?
A: While continuous ECG monitoring may make us (as doctors) feel better, it probably does not help in reducing the arrhythmia risk. On Holter, the EADs are a special type of premature ventricular contraction (PVC) that occurs during a very specific time (during the previous T wave). There area advance algorithms which can detect such PVCs with specific timing. However, the added expense and time is probably no better than the QTc on the resting ECG.

Q: I would like to know the opinion of the cardiologists on how important it is to screen monthly for all three electrolytes (K+, Mg++ and ionized Ca++) versus screening monthly for K+ only and then checking other electrolytes when K+ is low? Please consider screening monthly for all three electrolytes is a significant hardship for most programs.
A: This is a classic question for a decision analysis. I think we need to go back to the primary data to adequate answer this. During the safety trials for bedaqueline and delaminid, it would be interesting to note how frequently various electrolytes abnormalities were seen. I am sure that the incidence of individual electrolyte abnormalities is reported, but probably not for combinations. For example, if hypokalemia, what is the likelihood of concurrent hypomagnesemia? Another way would be to do a sensitivity analysis: knowing the cost inputs for electrolyte monitoring, how high must the rate of concurrent electrolyte abnormalities be for it to be cost-effective to adopt a "test all" strategy. Hopefully the folks to have access to the primary data from the trials are following along. Sorry I don't have a precise answer right now.

Q: A second question, given the strong potential of the injectable agents to result in electrolyte wasting and hypokalemia, is there benefit in giving a small daily supplement of potassium, magnesium and calcium?
A: I agree with Dr. Jachym. I think that there may be higher risk in prescribing adjuvant electrolyte replacement. I think we can be comforted that the safety data suggest the medicines are safe when monitored. Prescribing the electrolyte replacements will probably not change the frequency of ECG monitoring and may contribute to polypharmacy (in patients already taking many medicines for their DR-TB). Encouraging a diet higher in potassium (bananas, dried fruit, avocados) may be a better approach.

Q: A third request for the cardiologists, can you give us some findings on ECG in respect to the new TB drugs that you would lead you to immediate hospitalization with continuous heart monitoring. I think most programs will hospitalize for QT intervals above 500 ms, but is this always necessary?
A: I would be concerned if the QTc interval was significantly long (>500 msec) in the presence of symptoms of arrhythmia, such as worsened palpitations, lightheadedness, or syncope. In the Bdq trials, the patients receiving Bdq had higher palpitations - though it is not clear if the palpitations were truly due to arrhythmias or just a heightened awareness of the heartbeat. Other specific ECG findings to cause concern include overt arrhythmias such as non-sustained (or sustained) ventricular tachycardia. However, when obtaining and ECG, this will have to be an opportunistic finding. If the clinical suspicion is high for arrhythmias, and the heart sounds/pulse are not regular, you may want to leave the ECG machine attached to the patient for a longer period of time to catch the arrhythmia. Routine hospitalization for QTc>500 msec is probably not necessary.

Please keep up the robust conversation!

Michael Rich, MD MPH Replied at 3:40 AM, 10 Jul 2015

Good pharmacovigilance practice is generally based on acquiring complete data from spontaneous adverse event reports, also known as case reports. The reports are used to develop case series for interpretation (and FDA definintion).

There are choices in pharmacovigilance systems and these are best described in “A practical handbook on the pharmacovigilance of medicines used in the treatment of tuberculosis. ENHANCING THE SAFETY OF THE TB PATIENT” (http://www.who.int/medicines/publications/pharmacovigilance_tb/en/ ). Versions of this book also exist in French and Russian, and much of the below comments are taken from this reference.

Spontaneous reporting is the most common form of PV is spontaneous (also called voluntary) which involves a health-care worker - or even the patient - reporting a drug-related reaction. The effectiveness of such systems very much depends on the patient volunteering this information.

Targeted spontaneous reporting uses a methodology that monitors and records all or a specific set of safety concerns in a defined population of treated patients, e.g. drug resistant TB patients on treatment.

Active PV is a more systematic and proactive form of safety surveillance. In active PV, events are elicited as part of patient monitoring using a set of questions and an array of laboratory/clinical tests at defined periods of time, before, during and after treatment. For the new TB drugs, the advice of the WHO is that active pharmacovigilance measures MUST be in place to ensure early detection and proper management of adverse drug reactions and potential interactions with other drugs. As a clinician, I strongly agree that active pharmacovigilance needs to take place, most cohorts of MDR-TB patients are going through active monitoring with ECGs and laboratory data anyways, so this is not difficult.

In its most comprehensive form of active PV is called “cohort event monitoring” or CEM. CEM is essentially an epidemiological prospective observational cohort study. CEM is not a requirement of the WHO or the drug companies, but is preferred when possible (Implementing CEM is not meant to be a barrier to start using the drug as long as clinical monitoring for drug safety can be in place.

Some programs are likely to choose a form active patient monitoring for drug toxicity (but not in the form of a prospective observational study, but as part of routine program clinical monitoring for drug toxicity) and reporting serious adverse events (SAEs). For me this should be the bare minimum, but full CEM should not be required of any program. CEM should be encouraged when resources are available.

To date the pharmaceutical companies are not requiring full CEM to be in place however there is general agreement that SAEs will be reported. More information on How To Access The Bedaquiline Donation Program: Step By Step and information on suggested pharmacovigilance for the Bdq can be found at the website http://www.stoptb.org/news/announcements/2015/a15_013.asp

For Dlm, pharmaceutical company has not published information on pharmacovigilance requirements.

I hope this is helpful on pharmacovigilance requirements and strategies.
Michael

Fraser Wares Replied at 4:44 AM, 10 Jul 2015

The need of monitoring of QTc is obviously not limited to patients on bedaquiline, but also to patients at potentially higher risk of cardiotoxicity. That is the case of some countries implementing shorter regimens for the treatment of MDR-TB, which include two QTc prolonging drugs (moxifloxacin and clofazimine). Findings from WHO visits to some of these countries confirm the feasibility of implementing ECG monitoring in the field, albeit in the context of operational research projects. Data from some of these observational studies will be reviewed by WHO later this year, as part of the process of updating the WHO TB treatment guidelines, and will provide some evidence on the safety of regimens based on these drugs.

Michael Rich, MD MPH Replied at 7:31 AM, 10 Jul 2015

I wish to respond to Tom Yate's “I understand the excess deaths in the BDQ phase 2 study were attributed to progression of TB disease. I would be interested in how confident people think we can be regards attribution of cause of death here?”

More data on the deaths in the phase 2 trial (trial C208) is presented in the “Anti-Infective Drugs Advisory Committee Meeting Briefing Document TMC207 (bedaquiline) Treatment of Patients with MDR-TB NDA 204-384 28 November 2012, which is available on the internet at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Dr...

Twelve deaths were reported from the C208 Stage 2 trial in total (i.e. irrespective of when deaths occurred). Of these, 10/79 (12.7%) came from the bedaquiline group and 2/81 (2.5%) from the placebo group (p=0.017) (intention to treat analysis). Despite detailed descriptive line listings of all deaths, the reasons for the imbalance in deaths between the two arms were not identified. It should be noted that medical autopsies were not done as part of the clinical trial.

Among MDR-TB patients started on treatment globally in 2009, only 48% were treated successfully, as a result of high frequency of death (15%) and loss to follow-up commonly associated with adverse drug reactions (28%).

I would be reluctant to say how confident we on the "causes of death" in the clinical trial C208; rather, the data from the clinical trial C208 supports that the benefit of bedaquiline likely outweigh the risks. The following do make me feel confident that the WHO and others like the FDA and EMA are making the correct decision on the risks and benefits in relation to the use of bedaquiline:
• Causes of death were varied and all but one occurred after the treatment period with bedaquiline.
• When added to a background regimen for MDR-TB, bedaquiline improves treatment outcomes by approximately 20% while adding little to the constellation of adverse effects seen in MDR-TB (modest increase in QT and increase in hepatic transaminases).
• The low death in the placebo arm may be a statistical outlier. The statistical difference in amounts of death in the bedaquiline vs placebo arms may not be due to high amount of deaths in the bedaquiline arm but rather the few deaths seen in the placebo arm. Compared to the global data, it is relatively rare to have a 2.5% death rate, the global average rates of death outcome was 15% in 2009. This low death rate is especially unusual given that placebo arm had a terrible response rate (proportion of conversions in MGIT at 72 weeks of all available data in trial C208 was only 47%).
• The 12.7% of deaths in the placebo arm was at least lower than the global average rates of death outcome, which was 15% in 2009.

We absolutely need Phase III trials to better understand the safety and efficacy of bedaquiline, with particular attention to mortality (including causes of death), in the treatment of MDR-TB. There is a good degree of confidence based on the existing evidence to date that the possible benefits of using bedaquiline outweigh the potential risk under the conditions described by the WHO in the interim policy guidance on bedaquiline. Because of the increase death in the bedaquiline arm of trial C208, the recommendation to use bedaquiline in adults with laboratory-confirmed MDR-TB when an effective treatment regimen cannot otherwise be provided should be followed.

Kobto Koura Replied at 7:59 AM, 10 Jul 2015

Dear all
Let me just step in to share The Union experience.
Since 2013, we are conducting a cohort study in 9 francophone African countries using the Bangladesh regimen with prothionamide continued during the whole treatment, and gatifloxacin replaced by Moxifloxacin 400 mg (one tablet daily if weight more than 40 kg. If not ½ tablet daily). The regimen includes clofazimine throughout. While Moxifloxacin has been shown to cause QT prolongation with an increased risk of ventricular arrhythmia, we found only one case report describing a prolongation of QT with clofazimine.
In the study, an electrocardiogram is performed before initiation of treatment and one week later. QTc is calculated according to the linear regression Framingham formula: QTc = QT + 0.154 (1-RR). We define QTc prolongation as QTc > 450 milliseconds (ms) in men and > 470 ms in women.
We have looked at preliminary data on QTc intervals in patients of three countries and found a slight but significant increase in mean QTc one week after initiation of treatment. There were four patients with a QTc prolongation at one week. However none of them had cardiac symptoms, and their regimen was not interrupted nor modified. At this point, those patients are still alive and they have either finished their treatment or their treatment is still ongoing.
Awaiting your comments and questions.

Michael Rich, MD MPH Replied at 8:18 AM, 10 Jul 2015

On Clofazimine and QT prolongation: I wonder if one week post start of treatment is to early to measure QT prolonging effects of clofazimine. Clofazimine has a long half-life and steady state levels of the drug are not reached for several weeks. Is there any analysis of measurements of QT intervals in the patients on the short MDR-TB regimens with moxifloxacin and clofazimine further out in treatment?

thanks,
Michael

Kobto Koura Replied at 9:58 AM, 10 Jul 2015

Hi Michael,
I agree with you that Clofazimine has a long half-life and it is very earlier to consider the measure at one week.
But we need to be careful about the hypothesis that Clofazimine has an impact on QT prolongation. We cannot use a report case to make this conclusion.
In contrast the effect of Moxifloxacine on QTc is well established and that is the reason we performed a second measurement very earlier, one week after treatment initiation.
For the patients with QTc prolongation, additional measurements have been performed and QTc was normalized.
One country has systematically performed a third measurement at one month. Analysis of the data of this country found a non-significant increase in mean QTc one month after initiation of treatment.
In the regimen we use Moxifloxacine at normal dosage. This is probably the reason we have few patients with QTc prolongation.
Regards

Michael Rich, MD MPH Replied at 10:11 AM, 10 Jul 2015

Thank you Kobto for these further comments. Very helpful.

Could the cardiologists comment if they would expect a dose response in QT prolongation with higher doses of Moxifloxacin? Normal doses for MDR-TB treatment is 400 mg per day. High dose is often 600 mg per day in adults 33 to 50 Kg and 800 mg per day in adults greater than 50 kgs.

Does anyone have any data on average QT prolongation in adults taking 800 mg per day of Moxifloxacin?

Thanks,
Michael

Dylan Tierney Replied at 11:57 AM, 10 Jul 2015

Posted on behalf of Peter Zimetbaum (edited for clarity)

Q: Could the cardiologists comment if they would expect a dose response in QT prolongation with higher doses of Moxifloxacin? Normal doses for MDR-TB treatment is 400 mg per day. High dose is often 600 mg per day in adults 33 to 50 Kg and 800 mg per day in adults greater than 50 kgs.

A: There is absolutely a reason to suspect a dose response for QT prolongation. So one would expect greater prolongation with the weight-adjusted higher dosages.

Syed Rizwanuddin Ahmad Replied at 11:58 AM, 10 Jul 2015

I want to respond to the question regarding clofazimine and QT prolongation. In 1986, the U.S. FDA approved clofazimine for the treatment of lepromatous leprosy. Use of clofazimine for the treatment of TB is an unapproved indication in the U.S. The U.S. FDA may permit an investigational drug to be used for the treatment of a patient by a physician under what is called SPIND (Single Patient Investigational New Drug) program. Clofazimine is available under SPIND for treatment of other mycobacterial infections in patients failing therapy. According to data presented at the IDWeek 2012,

“Between 2005 and 2011, the FDA granted 649 SPINDs for clofazimine to treat mycobacterial infections, of which 350 were available for review and 216 provided adequate clinical information for safety assessment. The study population included 147 females, 59 males, and 10 unreported genders with positive sputum or skin mycobacterial cultures at diagnosis to evaluate adverse events reported for clofazimine-containing regimens. Median age was 60 years (range, 3-82 years); all patients were HIV negative.”

…….

“The majority of patients were on clofazimine (50mg or 100mg daily) for 12, 18, or 24 months, which was administered in combination with a number of other agents, primarily antibiotics. Of the 216 patients, 58 patients (27%) had completed treatment; 77 (36%) were on treatment; and 33 (15%) had discontinued due to AEs or ineffective treatment. There were 47 (20%) deaths that were reported by investigators to be unrelated to clofazimine; however, the actual cause of death was not stated.

Follow-up sputum cultures were available for 53 patients (25%); of these, conversion to negative culture occurred in 34 (64%). Adverse events reported in 68 of 208 patients (33%) included skin pigmentation (37, 54%), gastrointestinal reactions (27, 40%), and other (4, 6%).
Use of clofazimine was found at doses well in excess of the labeled dose for leprosy. Torsades de Pointes was reported in 7 of 11 patients taking 300-400mg/day—three to four times higher than the recommended labeled dose of 100mg/day—“suggesting that clofazimine should not be used at high doses,” they concluded.”

Ref:
http://www.empr.com/idweek-2012-adult-infectious-diseases/more-data-needed-on...

In the poster abstract session, during the IDWeek 2012, the study investigators (all from the US FDA) made the following conclusion:

“Adverse events associated with clofazimine were reported in one-third of patients. Conclusions cannot be drawn about the safety or efficacy of the drug for treatment of mycobacterial infections in this SPIND population. A randomized controlled trial with reliable clinical endpoints is warranted to evaluate the risk and benefit of clofazimine in the treatment of mycobacterial infections.”

Ref:
https://idsa.confex.com/idsa/2012/webprogram/Paper34354.html

Does anyone know of more recent data on clofazimine.

Hope this is helpful.

Best wishes,

Rizwan

Syed Rizwanuddin Ahmad, MD, MPH, FISPE, FCP

Pharmacovigilance Consultant with a Special Interest to Strengthen National Medicines 
Regulatory Authorities in Resource-limited countries
Ex-Consultant/Safety Reviewer, U.S. FDA (1998-2013)

Associate Professor (adjunct), Rutgers School of Public Health, NJ, USA

Assistant Professor (adjunct), Georgetown University School of Medicine, Washington, DC, USA

www.drugsafetyconsultant.com

Dylan Tierney Replied at 12:48 PM, 10 Jul 2015

There is a clear need to better understand the toxicity of anti-TB agents singularly and in combination.

I’ve never seen a conclusive list of QT prolonging anti-TB drugs ranked from most prolonging to least. I could take a guess based on my understanding of the literature of the older drugs: thioridizine > moxifloxacin > levofloxacin > clofazimine. The problem is that there isn’t a comparative head-to-head study in a uniform population of patients to give us really accurate information. Panelists or others in the forum, please feel free to debunk (or inform) my ranking, as it is off-the-cuff.

As far as the new drugs go, it’s not clear how to rank delamanid and bedaquiline in the list. Both are associated with QT prolongation. In a clinical trial of delamanid (Trial 204), about 10% of participants receiving the drug experienced QT prolongation, but only one individual developed QT prolongation over 500 ms. By comparison, in the Guglielmetti study, 20% of people taking bedaquiline experienced a ≥ 60 ms increase in QT interval. No arrhythmias were noted in either study, as has been previously mentioned by Gene Kwan. The numbers of subjects studied are too small to draw any comparative conclusions in my opinion. Further, there is little in the way of comparison to the older drugs.

Maybe even importantly than developing an individual ranking of QT prolonging effects, we need to know the toxicity of these drugs when they are combined because DR-TB treatment requires combined therapy. I fear, however, that this type of information will come to light slowly, especially for the newest drugs. While there are NIH ACTG trials looking at bedaquiline and delamanid in combination with each other and older drugs, it will likely be at least a year before results are made public. Pharmacovigilance results through compassionate use may be a faster way to arrive at the critical information but Otsuka, the maker of delamanid, has banned the compassionate use delamanid and bedaquiline together out of fears for compounded toxicity.

Judith Thermidor Replied at 4:23 PM, 10 Jul 2015

Tuberculosis can have effects in peripheral blood that mean patients with TB are often also anemia. So, if we conduct a screening to get a comparison with tuberculosis/anemia and tuberculosis/without anemia to deduct the QT prolonging effects is due from anemia or it is a toxicity of anti-TB drugs.
Kind Regards,
Judith Thermidor

Michael Rich, MD MPH Replied at 7:29 PM, 10 Jul 2015

More information on the support of QT prolongation attributed to clofazimine can be found in an additional safety finding in the C209 study also presented in the “Anti-Infective Drugs Advisory Committee Meeting Briefing Document TMC207 (bedaquiline) Treatment of Patients with MDR-TB NDA 204-384 28 November 2012, available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Dr... and reproduced below:

"The effect of concomitant use of clofazimine and bedaquiline on QTcF findings in C209 was evaluated using descriptive statistics for changes from reference in QTcF in subgroups by concomitant use of clofazimine. For concomitant use of clofazimine, subjects were included if they were using clofazimine at Week 24 and had an ECG assessment at Day -1 (reference) and Week 24. The subgroup of subjects without concomitant clofazimine use included subjects who did not use clofazimine at Week 24 and had an ECG assessment at Day -1 (reference) and Week 24. Mean increases in QTcF at Week 24 were larger in the 17 subjects who were using clofazimine at Week 24 (mean change from reference at 0 h of 31.94 ms) than in subjects who were not using clofazimine at Week 24 (mean change from reference at 0 h of 12.28 ms)"

While the numbers are small of patients taking clofazimine in Study C209, I think the large effect might put clofazimine high in in Dylan Tierney's suggested list of antiTB drugs that cause QT prolongation. This combined with the information provided that by Syed Rizwanuddin Ahmad above that "Torsades de Pointes was reported in 7 of 11 patients taking 300-400mg/day—three to four times higher than the recommended labeled dose of 100mg/day" make clofazimine an obvious drug to take extra precaution when combining with other anti-TB drugs that prolong the QT interval.

Prof.Dr.Matiur Rahman Replied at 12:19 AM, 11 Jul 2015

Excellent discussion by worthy colleagues.
Certainly there is reported arrhythmia on using new anti TB drugs but the benefits outweigh the hazard of arrhythmia in small number of patients which can be easily avoided by proper cardiac evaluation by a cardiologist or physician having experience in cardiology and proper monitoring while on bedaquilin.

Syed Rizwanuddin Ahmad Replied at 11:14 AM, 11 Jul 2015

Dear All,

We all know that the treatment of MDR-TB poses a special challenge with the existing therapy. No one can deny the urgent need for newer medicines with shorter courses and better safety profile.

On the question of excess deaths and overall safety of bedaquiline, I want to refer the group to the presentation made by the U.S. FDA’s medical reviewer during the FDA’s Anti-Infective Drugs Advisory Committee (AIDAC) meeting on November 28, 2012: Her concluding slides stated:

• A greater number of deaths in the bedaquiline arm is concerning. An etiology of the imbalance could not be determined from the current safety data.
• A major proportion of deaths is attributed to worsening of the underlying condition.
• The role of bedaquiline in deaths where hepatotoxicity and cardiac failure are contributory could not be ruled out. Association is difficult to determine because of the underlying condition, other co-existent medical conditions, and concomitant medications.
• Bedaquiline causes QTcF interval prolongation.
• The risk of QT interval prolongation, when bedaquiline is given with other QT prolonging medications, is additive.
• Bedaquiline can cause hepatotoxicity. Conditions and medications associated with hepatotoxicity could pose additional hepatotoxic risks.
• Like many drugs used to treat MDR-TB, bedaquiline’s safety risks require judicious patient selection and active monitoring.

Ref: The Food and Drug Administration. Slide presentation for the November 28, 2012 meeting of the AIDAC. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Dr.... Accessed July 11, 2015.

I fully agree with Dr. Michael Rich that “We absolutely need Phase III trials to better understand the safety and efficacy of bedaquiline, with particular attention to mortality (including causes of death), in the treatment of MDR-TB.”

We know that the US FDA granted bedaquiline a “fast track” approval and by law the company has to conduct a confirmatory trial that can bring some clarity to the question of excess deaths observed in the bedaquiline arm in the pivotal trial. However, the results of this confirmatory trial is not required until 2022. Given the high risk benefit ratio of bedaquiline based on the current evidence, I agree with the WHO interim guidance recommendation that Cohort Event Monitoring (CEM) provides the most complete and comprehensive data and is therefore the recommended approach to active pharmacovigilance for introduction of bedaquiline. Let’s hope that relevant individuals belonging to the NTP and the national medicine regulatory authorities in countries where newer anti-TB drugs are introduced receive adequate training in active pharmacovigilance.

Thank you again for organizing this expert panel and the useful discussion.

Rizwan

Syed Rizwanuddin Ahmad, MD, MPH, FISPE, FCP
Pharmacovigilance Consultant with a Special Interest to Strengthen National Medicines Regulatory Authorities in Resource-limited countries
Ex-Consultant/Safety Reviewer, U.S. FDA (1998-2013)
Associate Professor (adjunct), Rutgers School of Public Health, NJ, USA
Assistant Professor (adjunct), Georgetown University School of Medicine, Washington, DC, USA
www.drugsafetyconsultant.com

Mulbah Tokpah Replied at 1:31 PM, 11 Jul 2015

Hi Dr.
Thanks a million for such a wonderful discussion. This information is very useful to me and will always be willing to get hold of such from you. Thanks so much.



Mulbah M. Tokpah

Dylan Tierney Replied at 9:24 AM, 14 Jul 2015

I would like to thank our panelists and all of our community members who participated in this excellent discussion. I learned a great deal from your shared insights and perspectives. Concerns about QT prolongation and cardiac arrhythmia are likely to become more and more prominent as access to new drugs increases. I hope that the issues that were raised during our week of discussion can be useful in guiding the development of a comprehensive approach to managing this important adverse drug effect.

I will draft a summary of the key points from the expert panel in the coming weeks and will share it on this website. In the meantime, I recommend reading an excellent review on QT prolongation recently published in the International Journal of Tuberculosis and Lung Disease and written by a couple of our panelists (link below).

Attached resource:

Dominique Kabengele Kayembe Replied at 1:11 AM, 17 Jul 2015

Dear All

Thank you very much for your insights on this matter. As part of its clinical expanded access (leading to registration of Bedaquilline by SA-MCC), South Africa presented its preliminary experiences with Bedaquilline (both efficacy and adverse events) that could be found on the 45th The Union 2014 Barcelona website: http://slideonline.eu/recordings/2014/14union/.

As shared in discussion, South Africa was not the only that used Bedaquilline after FDA registration. Is there somebody among the group who knows about other countries experiences' reports (though preliminary) and could share them with us? Will also appreciate that any who had access to this article Int J Tuberc Lung Dis. 2015 Apr;19(4):385-91. doi: 10.5588/ijtld.14.0335. QTc prolongation and treatment of multidrug-resistant tuberculosis. Harausz E1, Cox H2, Rich M3, Mitnick CD4, Zimetbaum P5, Furin J1 could share it with us!

Dr Dominique Kabengele Kayembe, MD, DTM&H, AAHIVS, DipHIVMan
Clinical Manager PHC/HAST, Eshowe District Hospital, KwaZulu Natal, South Africa

Erica Lessem Replied at 4:29 PM, 21 Jul 2015

Hi all, this is a great discussion.

Dominique and all, I know colleagues from places like Mumbai, Georgia and
France have extensive experience with bedaquiline as well, but am not sure
if they are on this listserve. If you send me your email (mine is
), I'd be happy to connect you.

Also if you send me your email address, I will be happy to share with you
the IJTLD article you indicate. (It is not open access otherwise I would
post it here).

It notes that QTc prolongation with delamanid is mild. This was also
confirmed on a call with Otsuka last week organized by RESIST-TB. The
article also explains that neither bedaquiline or delamanid QTc
prolongation is associated with clinical events or torsades de point
arrhythmia (as I think others on this thread have noted). It also lays out
strategies for clinical and programmatic management of QT effects for these
and other MDR-TB drugs. So my question is, why is Otsuka still denying
patients access to delamanid if bedaquiline is or has been used under their
so-called "compassionate" use program, while we wait the several years for
the ACTG Study A5343 to be completed which will assess their concomitant
use? Compassionate use, by definition, involves patients in extreme
circumstances without other good options, so different risk-benefit
calculations apply. If a patient with pre-XDR, XDR, or severe toxicity from
an MDR drug, is informed of the risk and consents to take on this risk, and
his or her doctor is willing to administer both delamanid and bedaquiline
and monitor the drugs and effect on QT closely, why wouldn't Otsuka be
giving them the choice to do so, particularly when without having both
drugs they would face protracted illness, ongoing infectivity, often
permanent disability, and potentially death?

Best,
Erica





-----

Erica Lessem, MPH
Director, TB/HIV Project
Treatment Action Group
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Ahmed Kamel Replied at 6:27 AM, 31 Jul 2015

I think that those with family hx of sudden cardiac death or hereditary channelopathy recive special care when treated by such drugs

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