The World Health Organization has set out plans to attempt to eliminate tuberculosis (TB) by 2030, Countries such as India have set more ambitious goals, pledging to eliminate the disease by 2025.

One major hurdle presents itself as a threat to this cause — drug resistance. Drug resistance may not only frustrate elimination efforts, but actually create a situation in which TB is even more of a threat than it is in its current state.

In 2017, ten million people fell ill with TB, with 1.6 million dying as a result. Multidrug-resistant TB (MDR-TB) is estimated to account for 558,000 new cases in that period, with a particular obstacle being resistance to rifampicin-based treatments — the most effective and most commonly used first-line medications across the globe. These cases are highly difficult to treat and make the goal of a TB-free world by 2030 more difficult to attain, let alone more ambitious national targets.

Multidrug-resistant TB (MDR-TB) is TB that does not respond to at least isoniazid and rifampicin. If the strain of TB develops further resistance against other drugs, it is referred to as extensively drug-resistant TB (XDR-TB). These strains are defined by the CDC as “resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin)”.

As drug-resistant strains become more common, our frontline medications become useless. In many developing nations, this may leave them with few resources to attempt to stop the disease because of the greater expense of second-line treatments. This may result in even worse levels of treatment adherence.

Lack of treatment adherence is a major factor in the development of drug resistance. In some instances, this is due to a lack of knowledge of the drug regimen, resulting in individuals not following the full course of the medication. Often individuals may stop as soon as symptoms alleviate. Other issues may be out of the hands of the individual, such as poor supply lines or expense of the medication.

Timely diagnosis of the disease is crucial. As soon as an individual is diagnosed, they can be treated; this also reduces the chances of the disease being inadvertently passed on to others through person-to-person contact. Those left untreated are not only more likely to pass on the disease, but also are more prone to severe health outcomes — even death — in particular if they develop other conditions alongside TB.

Drug resistance is an issue complicating the fight against TB, but also exacerbating crises linked to numerous other diseases worldwide. It is a problem which threatens to negate many of the advances made in global medical campaigns, leaving frontline medications useless, and causing disease cases to surge.

 

A new strain arises in South Africa

Drug resistance and mutation within a viral or bacterial strain is most commonly thought of as simply a resistance to a type of medication. However, the mutation of a genome may have other effects that make the strain more difficult to treat.

In South Africa, a Lancet study identified an MDR-TB strain undetectable to WHO-endorsed commercial tests. The study found that thirty percent of the MDR strains harboured the Ile491Phe mutation in the rpoB gene, which is associated with poor rifampicin-based treatment outcomes.

This strain shows how easy it is for drug resistance to develop. Bacteria and viruses have a chance at mutation within their genomes with every single replication. These mutations may have no effect on encoded genes at all, they could however result in changes that leave the pathogen more resistant to a given medication. There may be a slight change that has no notable effect, or there may even be an alteration that disrupts vital mechanisms within the cell, rendering it unviable and hence dying.

In rare circumstances the mutation may be beneficial, making the cell more resilient to the effects of a medication. Though these events are rare, given the sheer number of bacteria multiplying — particularly considering that ten million individuals are infected per year, each hosting countless bacterial cells — they can occur with relative frequency, giving rise to new drug resistant strains.

In the case of the South Africa strain, a single amino acid has been changed. In this case an isoleucine has been replaced with a phenylalanine. While the alteration is minor, it can drastically alter the way in which the bacteria interacts with particular chemicals, in this case, reducing the effect of rifampicin treatments.

The study warns that this mutation, and therefore the resistance to treatment, is not detectable by diagnostic techniques currently used in South Africa. Consequently, this strain has been misdiagnosed and therefore treated with ineffective first-line therapies. Such an oversight is allowing for the resistant strain to proliferate, amplifying the number of resistant cases of TB in South Africa.

 

Multi-drug resistant TB, a dangerous rush to develop new medications

The rapid increase in MDR-TB cases necessitates a rapid response in the development of new treatments. This creates a kind of medical arms race in which research must keep up with the ever changing drug resistant strains.

Treatments for MDR-TB are desperately needed. When a prospective treatment for MDR-TB is announced, it faces high expectations with calls of “miracle cures” commonplace among media reports.

The term has been used in the instances of TB medicines such as bedaquiline. “I have already seen media reports from India which call bedaquiline a ‘miracle drug,’ said Dr Madhukar Pai, Director of McGill Global Health Programme, in comments to The Indian Express. ‘This worries me – terms like ‘miracle drug’ should not be used lightly.” (Dr Pai was interviewed about TB for HII in 2017.)

Bedaquiline was the first medication since rifampicin in the 1960s to have been developed specifically for the treatment of TB. Differing from previous TB treatments, bedaquiline has an altogether different mechanism of action. The drug specifically targets an enzyme within the Mycobacterium tuberculosis bacteria called ATP synthase.

The ATP synthase enzyme is responsible for the conversion of adenosine diphosphate, along with an inorganic phosphate molecule to create adenosine triphosphate, or ATP. ATP itself is used in chemical reactions within the body — or in the case of TB, the cell — as a source of energy. Without energy reserves, the TB bacteria gradually die off.

Bedaquiline may form the last line of defence against MDR-TB, with ever more trials showing positive results. One trial which took place in Belarus found bedaquiline to have more than a ninety percent cure rate when given in combination with other TB medicines. By comparison, currently used TB drugs were shown to be effective in just over half of cases.

There is, however, a considerable drawback to the use of bedaquiline, one which is acknowledged by the WHO. “Bedaquiline has been reported to disturb the function of the heart and liver in particular”, the WHO says. In stage II human trials, deaths among those in the bedaquiline treatment group were higher than those taking the placebo control.

For these reasons the drug is considered by the WHO to be a last resort treatment, and recommendations are in place that any individual put onto treatment with bedaquiline is actively monitored for any abnormal symptoms.

 

Hope for the future already being quelled?

Literature review studies compiling all current evidence on the cardiotoxicity of bedaquiline have found that no deaths have so far been attributed to the cardiotoxicity cited by the WHO. Though cardiac arrhythmia is noted as a side effect, its severity has not yet been documented to go as far as causing the death of a patient. The rise in deaths associated with the drug during the studies is therefore in need of greater scrutiny and warrants further study.

Other treatments currently approved in some countries, such as delamanid, have seen far less notable results. Results from a sixth-month trial indicated that 87.6 percent of those being treated with delamanid in conjunction with background treatments became TB negative. The placebo control group, only receiving the background treatments were 86.1 percent TB negative. Such a negligible result after such a long period of research is a worrying prospect, leaving fewer viable treatments in the instance of drug resistance.

The study published in The Lancet has even more grave implications. Six of the South African isolates found during the study contained four distinct mutations which the researchers believe are potentially associated with decreased bedaquiline sensitivity.

To have already identified mutations that are implicated in potential drug resistance to medications that have not yet been widely used is a concerning prospect. This could result in bedaquiline quickly becoming obsolete in certain areas, namely in South Africa where the study found the initial outbreak.

Bedaquiline was released in India only a few years ago, yet resistant strains of TB are already emerging. Attribution: Ministry of Health and Family Welfare

Resistance to bedaquiline may have either spread, or independently mutated within India. Patients with bedaquiline resistance have been detected at Sewri hospital and Hinduja hospital in Mumbai. Access to the drug in India is currently limited, though if resistant strains spread it may already have lost its effectiveness in a number of cases.

The Ile491Phe mutation arose independently within at least two strain lineages just in South Africa. In other nations with high burdens of TB such as India, further strains may have developed bearing similar, if not the same mutations. If this can occur in the mutation that made detection using diagnostics far more difficult, it can occur in the mutations resulting in resistance to bedaquiline.

Drug resistance may be occurring far faster than anticipated, though it is not being studied enough to be recorded. Pockets of drug resistance in which bedaquiline is no longer effective could give rise to the potential that areas such as South Africa and India could harbour entirely untreatable strains. If these strains were to spread — an event that can occur far faster in the modern day where air travel could put drug resistant strains in every corner of the globe in a mere 24 hours — drug resistance could advance faster than we have the capacity to keep up with it.

 

Economic impacts of drug resistant TB

First-line therapies are the cheapest means of treating TB. As these forms of treatment become unviable, second-line treatments must be used. In strains deemed to be XDR-TB, resistance is present to at least one second-line treatment, making even these therapies unviable. Many of these therapies are far more expensive as well as being available only in limited quantities in developing nations.

The CDC estimates the direct treatment costs (in 2016) average from USD 18,000 to treat drug-susceptible TB to USD 513,000 to treat the most drug-resistant form of the disease, XDR TB. This is a 2,800 percent increase from the cost of treating standard TB.

The burden of drug resistant TB is primarily reported in Eastern Europe and Central Asia, though pockets of high percentages of cases are recorded in South Asia, East Asia, Africa and South America. These figures may be misleading due to the inclusion criteria. Notably, countries such as India have not declared disease cases reported at private tuberculosis clinics, which may have resulted in significant underreporting of MDR-TB cases.

Developing nations may be all but completely unable to handle the costs. In many countries grossly inadequate public health budgets are already stretched between numerous infectious diseases, as well as facing a rising tide of noncommunicable conditions. Allocating the budget necessary for a potential USD 513,000 per individual with XDR-TB could financially cripple the health system.

A consistent issue that must be faced in the years going ahead is that drug resistance may arise anywhere that TB cases exist. Therefore, any global planning and international cooperation must take this into account. If TB is to be eradicated then arrangements must be put into place to quickly address drug resistance wherever it occurs.

In this instance cooperation between pharmaceutical companies, governments and charities is essential. Such is the case in the TB Drug Accelerator (TBDA) group. The organisation combines eight research institutions as well as nine pharmaceutical companies — including members such as Merck and Sanofi — under the coordination of the Bill & Melinda Gates Foundation.

Drug resistant strains of TB could occur anywhere in the world and if left unaddressed could eventually cross international borders. It is therefore imperative that developing nations are assisted in shouldering the economic burden of treating these XDR-TB strains, as any country still harbouring them may go on to spread the infection to countries that may have already declared the disease to be eradicated.