What is multidrug-resistant tuberculosis (MDR-TB) and when did it first arise?
MDR-TB is tuberculosis, a mycobacterial infection, that has developed resistance to two important and powerful first-line anti-TB drugs, INH and rifampin.
TB, like most microbes, has the ability to mutate and develop resistance to antibiotics when they are exposed to these antibiotics. The risk that microbes will develop these types of resistance mutations is increased by many factors, including a patient being given the wrong medicines or an incomplete regimen or when therapy is interrupted for any reason – e.g. a drug shortage or stock out, or the patient being unable to continue the medicines because of side effects or cost.
INH resistance was first identified less than 20 years after the introduction of INH. Within a few years of the discovery of rifampicin in 1966, TB resistant to this drug was also identified.
In more recently years, strains of TB with additional drug resistances have been identified, including extensively resistant TB (XDR-TB) in 2006 and in 2009, a strain of TB resistant to all drugs used to treat TB at the time this strain was identified.
Given, the increasing number of resistance mutations and the increasing number of people with resistant strains of TB, it is clear that new, more effective and safe drugs are desperately need to treat this growing epidemic.
How many people are thought to be affected by MDR-TB and how has this number changed over the past half a century?
It is thought that there were more than 310,000 cases of MDR-TB among patients who were notified of their TB disease in 2011. When considering patients who never were diagnosed with TB and those with TB in places other than the lungs (extra-pulmonary TB), the estimation of patients with MDR-TB is even higher – up to 790,000.
This number is rapidly growing and is focused in several countries, with India, China, the Russian Federation and South Africa, accounting for nearly 60% of cases. However, other countries are reporting more and more cases of MDR-TB, making this a global epidemic.
Globally, approximately 3.7% of new cases and 20% of previously-treated cases have MDR-TB. However, in some countries, the percentage of newly diagnosed patients with TB have MDR-TB – for example, in Belarus 32% of patients with newly diagnosed TB have MDR-TB and in Kyrgyzstan, where MSF treats MDR-TB with a special focus on pediatric cases, 26.4% of newly diagnosed patients have MDR-TB.
MDR-TB is transmitted among populations – further highlighting the importance of rapidly acting to implement proper diagnostics and more effective treatment to stem this growing pandemic.
One of the most important issues in estimating the true burden of MDR-TB is inadequate diagnostics. Globally, fewer than 1 in 5 patients who have MDR-TB are ever correctly diagnosed. Without accurate and timely diagnosis, patients do not receive the right treatment and the infection can continue to progress – leading to disability and all-too-often, death.
Further, as TB is an airborne contagious disease, patients who have MDR-TB will continue to transmit this disease without proper treatment.
MDR-TB has traditionally been diagnosed by culturing the TB microbe and testing its resistance to certain antibiotics in a centralized lab. However, diagnosing MDR-TB based on culture can take more than 2 months, as TB is a slow-growing mycobacteria, and also requires significant laboratory infrastructure to ensure sample transport to the central lab as well as to ensure adequate lab equipment and supplies for culturing TB.
These resources do not exist in many countries and so many patients go undiagnosed. Fortunately new technologies are emerging that will help to improve the rapid diagnosis of TB and MDR-TB in low-resource settings. These technologies include Xpert TB-Rif which can diagnose TB and MDR-TB in just 2 hours and can be used at decentralized health facilities.
The WHO estimates this technology will triple the number of MDR-TB diagnoses made. This technology is being rolled out in South Africa and other countries. In MSF projects using Xpert, we have seen a 3-fold increase in number of MDR-TB patients diagnosed in our project in Zimbabwe and we have also seen the time from testing to treatment cut dramatically.
Although Xpert represents an important advance that should be rapidly supported in countries, it is far from a perfect test. Xpert is not a true point of care test and cannot be decentralized down to the most primary health care level, where 60% of patients with TB are diagnosed. Further, the cost remains high which may hamper rapid scale up of this important technology.
Xpert also does not do as well diagnosing patients who do not have a high burden of TB bacteria in their lungs (as is the case often with HIV co-infected patients) and other fluids besides sputum cannot be used, which is a problem for diagnosing pediatric patients who often cannot produce sputum.
We need a more affordable test that can be used at the primary health care level, is accurate using other body fluids and ideally will be point of care.
Why are we seeing unprecedented numbers of people with MDR-TB?
Please see reasons stated above including inadequate diagnostics, improper treatment and treatment interruptions leading to the development of MDR-TB as well as MDR-TB being increasingly transmitted in communities. Lack of political will and funding, inadequate diagnosis and weak health systems and TB programs are accelerating the MDR-TB pandemic.
Should we be worried by the levels of MDR-TB?
Absolutely. MDR-TB is a potentially deadly disease that is transmitted via the air. The current tools we have to diagnose and treat MDR-TB are not being adequately utilized because of inadequate funding, lack of political will and tools that are far from optimal.
We should not only be worried that this disease is claiming far too many lives and is on the rise, but we should also be worried that MDR-TB is a curable disease and that its spread can be stopped – but only with dramatically increased political will and resources.
We should be very worried that politicians and other leaders in high-burden countries and wealthy countries are not prioritizing this disease and reacting rapidly with adequate funding and a push to urgently scale up current diagnosis and treatment as well as strengthen TB programs to make way for new, more effective tools and medicines to diagnose and treat MDR-TB.
Dr Chinasylova, TB doctor for Médecins Sans Frontières in Swaziland, has recently said, “Getting better treatment is beyond urgent, but we are not seeing anything like the level of prioritisation required to make this a reality.” Why do you think MDR-TB is not being prioritised?
The burden of TB is primarily in low- and middle-income countries. Within these countries poor and marginalized populations are disproportionately affected. This means drug companies do not see TB as a key market for which to develop drugs and countries may not feel the political pressure necessary to improve TB programs.
There also seems to be a certain degree of fatalism attached to MDR-TB treatment and care. It is not simple to diagnose and treatment is long, arduous and expensive. This may be used as a justification for not fully scaling up a package of diagnosis, treatment and care for MDR-TB in low and middle-income countries. But this is not an excuse to let people living with the disease die and to let the epidemic grow.
This lack of focus on MDR-TB is not limited to implementing countries or drug companies. The Global Fund to fight AIDS, TB and Malaria, the major international funding mechanism for MDR-TB, providing 90% of international funding, is not prioritizing MDR-TB and has recently reduced the share of funding going to TB.
With a major replenishment conference coming up, the Global Fund is not sending the right message about TB to donors. The message instead should be that we are facing an historic opportunity to turn this epidemic around, but without increased funding, we will miss this window and new tools, including powerful new medications, may be squandered.
What problems are there with current treatments for MDR-TB?
Current treatment for MDR-TB is usually given for 2 years or more and includes eight months of painful daily injections. The fact part of the regimen includes injections hinders decentralization of treatment and often requires the patient to make daily trips to a health center that may be far away.
Some countries require hospitalization of the patient, further complicating care, increasing costs and making treatment more difficult for patients as during this period they cannot be working or caring for their family.
The medicines used cause many side effects such as extreme nausea and vomiting, confusion or psychosis and hearing loss and deafness. A typical MDR-TB regimen costs around $5000 USD which doesn’t even include medications to manage side effects such as anti-nausea medicines.
Please can you give a brief introduction to the two new TB drugs bedaquiline and delamanid? What research is needed to determine the best way to use these new drugs?
Bedaquiline and delamanid represent members of two entirely new classes of TB medications. Both drugs look extremely promising and may dramatically improve the efficacy of treatment for MDR-TB. They are the first drugs developed for TB in over 40 years. These drugs also appear to be better tolerated than many of the current medicines currently available to treat MDR-TB.
The fact that these are new classes of medicines that have not been previously used to treat TB means that these drugs retain activity as TB has not yet had a chance to develop resistance to these drugs. With several new classes of TB medicines as well as important repurposed drugs that are effective in treating TB, we have a unique opportunity to create extremely effective TB regimens for MDR-TB that maximize likelihood of achieving cure while reducing the chance that TB will develop further resistance to medications while on treatment.
The potential is there, but further research is needed to fully realize the promise of these new drugs. First, important phase III trials of both drugs are currently on-going and these studies will give us more information about the safety and efficacy of these drugs in studies that include many more patients than in already-completed phase II studies.
But patients with forms of TB including XDR-TB and patients with MDR-TB who cannot tolerate current MDR-TB medicines cannot wait for the next several years for these phase III studies to be completed and have little to no other options. Time is of the essence for these patients and given the promising results from the phase II studies of these drugs it is critical to ensure access to these new medications now for this particular patient group.
On the basis of phase II data, bedaquiline has received accelerated approval from the FDA for use in just such patients. The originator company of bedaquiline, J&J, will be required to complete phase III studies to obtain full FDA approval. Delaminid is awaiting approval from the European Medicines Agency (EMA).
Importantly, we do not yet have information about the safety of combining these two new drugs together. This sort of data is urgently needed as once both drugs become approved and available, physicians desperate for potential regimens for their patients with resistant TB may begin to use the two drugs together.
Additionally, the ability to combine these two drugs may be the key to constructing regimens for MDR-TB that will be maximally effective while minimizing risk that TB will become resistant to these new drugs. Manufacturers must work together to rapidly trial the safety of combining these two new drugs.
How do you think the future of MDR-TB treatments will develop?
With multiple new and repurposed drugs with very promising activity against TB in clinical trials and entering the market, the TB drug development pipeline is more active than it has been in a lifetime. Promising compounds in preclinical trials are being investigated and lead organizations are beginning to test some of these compounds in combination – thus accelerating the best candidate regimens (as opposed to single drugs).
But it is not a given that development will continue to grow or even be maintained. Every year, TB R&D funding falls far short of targets and many drug companies do not see TB as a lucrative market as the majority of TB cases are found in poor countries. There is a real risk that manufacturers may abandon potentially powerful drugs in the pipeline because these drugs do not sufficiently fit into their business plan in terms of profit.
Other drugs that have been developed for other infections and repurposed for TB may also not reach full potential because of lack of resources to fund trials and build sufficient evidence to obtain an indication for treatment of TB. Again, this is in part because many drug companies are not willing to invest the resources necessary to build such a portfolio.
The fact that such an important and growing disease is de-prioritized by some of the largest and wealthiest pharmaceutical companies in the world highlights a fundamental flaw in how R&D is incentivized. In our current system, R&D is driven by eventual profitability of a drug as opposed to global need. Thus TB is not the only global pandemic where R&D does not match the burden of disease. The way R&D is incentivized must be fundamentally changed in order to find a sustainable solution to this pervasive problem.
So while I think there are many reasons for optimism and excitement, the future of MDR-TB treatments is far from sure and it will take appropriate funding, political will and public pressure to ensure that drug companies, countries and other key actors are held accountable for bringing promising TB therapies to the patients in desperate need.
Please can you outline the ‘Test me, treat me’ manifesto recently launched by Médecins Sans Frontières? What is the aim of this public manifesto and who has signed it?
The “Test me, treat me” manifesto was written by patients living with MDR-TB and their clinicians and it demands scale up diagnosis and treatment of DR-TB now; to improve drug treatment regimens to be shorter, less toxic and more effective; and to have the financial support and political commitment in place to achieve this.
The manifesto has been signed by people living with and affected by MDR-TB and health care providers across the world (see http://msfaccess.org/TBmanifesto/).
The manifesto will be given to key actors including donor and implementing country governments as a call to take the necessary action now to save lives by improving cure rates for those living with the disease and steming the spread of the epidemic.
Do you think it will ever be possible to eradicate MDR-TB?
I think it is possible to control this deadly epidemic – but this will require dramatically changing the status quo. We need to change the way we diagnose people with TB and rapidly change guidelines to incorporate new powerful diagnostic tools as well as promote active case finding and contact tracing.
For those diagnosed appropriate treatment must immediately be instituted. Normative bodies and country TB programs must rapidly change treatment guidelines to accommodate new research and new drugs coming to market – especially for those patients with few or no other options for treatment.
And of course, all this will take political will and adequate funding from both implementing and wealthy countries.
Where can readers find more information?
MSF TB Manifesto http://msfaccess.org/TBmanifesto/
MSF Access Campaign http://www.msfaccess.org/our-work/tuberculosis
About Jennifer Cohn
Jennifer Cohn, MD MPH, is the medical co-ordinator of MSF’s Access Campaign, based in Geneva. She has worked with MSF on HIV policy and medical support in Kenya, Uganda and Malawi.
She is also an assistant professor of Infectious Diseases at the University of Pennsylvania School of Medicine and has provided clinical care to people living with HIV in the US and Kenya for the past 6 years.
At University of Pennsylvania she was the Director of the Global Health Equities Residency Track and also served as the PI on two recent operational research projects focused on HIV care in Kenya.
She is published in peer-reviewed journals including Science, the Lancet and JAIDS. Jennifer received her MD and specialty training at University of Pennsylvania School of Medicine and her MPH at Johns Hopkins University.