The changing landscape in drug resistant-tuberculosis: an analysis of recent advances

KEYWORDS:

• Tuberculosis
• drug resistant
• MDR-TB
• XDR-TB
• new anti TB drugs and regimens
• advocacy

Introduction

Despite being considered one of the major infectious diseases in terms of mortality and morbidity, tuberculosis (TB) has not been among the priorities of the scientific community and pharmaceutical industry for decades [1].

Being a disease mainly affecting the poor, in rich countries, TB was relegated to an inconvenient truth in big cities, linked to socioeconomic inequalities and high stigma conditions like homelessness and drug addiction. When it comes to developing countries, the disease was hitting all of society. In these settings, TB was striking hard at the poor, predominantly in their prime working years, affecting their families and compounding poverty in those with fewer opportunities. The impact of TB in countries with high HIV burden is particularly devastating. For all these reasons, unlike HIV or other diseases, advocacy has been lacking for persons with TB, until very recently.

When TB became appealing again

In 2006, the U.S. Centers for Disease Control and Prevention established the term ‘extensively drug–resistant’ (XDR) TB [2] and later, WHO defined XDR-TB for those TB specimens resistant, at least, to rifampicin (RIF) and isoniazid (INH) plus resistance to any fluoroquinolone and, at least one second-line injectable drug [3]. But the strong jolt came shortly afterwards, when a deadly outbreak of XDR-TB in South Africa was published in the literature [4]. The mortality rate was 98% among people living with HIV, in less than 16 days after diagnosis; most patients were infected by similar TB strains.

This was definitely a call to arms. Consensus and baseline documents on the management of DR-TB became the foundations of understanding between leading TB organizations worldwide. DR-TB could not be disregarded by ministries of health: most countries at different speeds started to manage DR-TB patients under program conditions. This marked a change in mentality, perspective, and recognition of the gravity of this disease.

In developed countries, resistance was not viewed as a great problem: low number of patients, drugs mostly available, and cases managed by well-trained physicians. In developing countries, however, the story was completely different; large numbers of DR-TB patients, limited availability of second-line drugs, and physicians were without experience on their use and toxicities [5].

Despite the good will of many physicians, such conditions and the absence of training increased the likelihood of committing errors that could end up increasing the resistance patterns [6]. Many patients died waiting for drugs to arrive or a bed in the reference center for DR-TB treatment. A wide primary transmission situation was brewing due to untreated or sub-optimally treated patients, plus almost a complete lack of contact tracing, spreading resistant disease in the community and hospitals.

The echoes of XDR-TB and beyond, high mortality rates, and the massive cost of its management stimulated the research for new drugs and ways to diagnose DR-TB. An unexpected window of opportunity was open for the first time in more than 40 years.

Main changes in the DR-TB panorama in the last 5 years

In early 2009, we wrote a review about the origins of the current DR-TB epidemic and an update on the fundamentals and quality standards for DR-TB management [5]. Almost seven years has passed, but the validity of most of that text still remains in force. We were asked for a five-year review and after decades of immobility, we were very modest with our expectations. We even mentioned: ‘It is unlikely that significant changes in the TB landscape will be witnessed in the next 5 years’ [5]. We certainly acknowledge our misperceptions as more changes have occurred in last 5 years than in the preceding 40 ones. This is the main reason for this lengthy editorial, where we will review what we think have been the most notable changes.

Changes in epidemiology and policy advances

In 2014, WHO gave some striking news in its annual epidemiology report [7]: DR-TB is present worldwide, and 50% of the current MDR-TB patients have been infected via primary transmission: patient to host. In the 2015 report WHO launched another jolt [8]: TB is now more deadly than HIV/AIDS, partly because of the high mortality rate in DR-TB. We are now paying the price of decades of lack of action in policy and research. But it is likely we still do not really know the true burden of DR-TB in key populations like children, grossly underreported and not treated [9].

The advances in TB diagnosis and reporting systems have made visible a problem that has remained invisible for decades. The current magnitude of the problem has provoked WHO and other international TB organizations to become more aggressive and ambitious with an ‘End of TB strategy’. Over these years, there has been a massive change, and that is the recognition of treating TB under ethical guidance in all populations as a moral obligation [10].

Advances in diagnosis

Genetic tests, highly specific and much more sensible than the traditional sputum smear, have revolutionized TB diagnosis. Specific regions of the bacillus DNA can be identified by different PCR techniques. GeneXpert, a real-time PCR device, fully automatic (hence little training needed), can yield results in 2 hours under minimal biosafety or laboratory requirements from pulmonary and extrapulmonary samples [11]. In December 2010, WHO first recommended Xpert MTB/RIF. Since then, the wide distribution of this technology created an unprecedented increase in TB and MDR-TB diagnoses as it can also detect the rpoB gene mutation conferring resistance to RIF. The recognition of RIF resistance as a proxy to MDR-TB (resistance to INH and RIF) allows the use of GeneXpert for surveillance purposes [12]. New prototypes, like GeneXpert-Ultra, present even better sensitivity (similar to liquid media), and GeneXpert-Omni is fully portable with the additional capacity to determine HIV viral load and diagnose Ebola.

Other PCR devices like the GenoType MTBDRsl have additive value of detecting mutations conferring resistance to RIF, INH, fluoroquinolones, injectables and ethambutol [13]. However, these devices need highly positive smears or cultures and a molecular biology laboratory. Both facts have relegated their use mainly to reference TB laboratories. Incoming prototypes will overcome some of this limitations and increase current capacities.

The next step in TB diagnostics might be whole genome sequencing, hence analyzing the whole genetic map of the TB bacillus. This is probably the way forward, especially considering the comparative low price and the potential of this test [14]. Unfortunately, our understanding of the genetic mutations conferring resistance to the current medications is still very limited.

Advances in treatment

Not a revolution, but certainly massive steps ahead in TB treatment have happened in these 5 years. For the first time in four decades, new drugs specifically designed against TB have appeared with the potential to replace historical drugs in susceptible or resistant regimens. Additionally, shorter and highly effective regimens against MDR-TB have been developed.

New drugs

Bedaquiline (Sirturo©) is a new drug from a completely new family, the diarylquinolines. It is mainly a bactericidal drug which blocks the ATP-synthetase in the membrane of the bacilli [15]. It is been proved under Phase IIb studies [16] and it is now used under compassionate use and program conditions with excellent results even in XDR-TB cases [17]. It was approved at the end of 2012 by the US FDA and is currently promoted by WHO under specific guidance [18]. Currently, it is only accepted for a period of six months which may limit its use in XDR or salvage regimens. The main problem currently identified is the increase in the QTc segment of the electrocardiogram which precludes its use under other certain conditions [19]. Cross resistance with clofazimine has been identified as well [20].

Delamanid (Deltyba©) is a new bactericidal and sterilizing drug that comes from the same family of antibiotics as metronidazole, the nitroimidazoles [21]. It was approved in 2014 by the European Medicines Agency. It inhibits proteins and mycolic acid biosynthesis. Delamanid seems to have the capacity to kill metabolically active bacilli and also the metabolically inactive bacilli, which are responsible for relapses [21] and might be a key drug in order to reduce the length of TB regimens [22]. Currently, its use is growing to be worldwide as promoted by WHO guidance [23]. It is also only accepted for a six-month period. The main problem identified is yet again, increase in the QTc segment, which hinders the combination with bedaquiline, moxifloxacin, and some ancillary drugs.

Pretomanid (previously known as PA-824) is also a nitroimidazole. It has been tested under different combinations and models yielding interesting results [24]. It is not yet widely used in TB patients but it is certainly a promising medication. The combination of pretomanid with moxifloxacin and pyrazinamide has yielded excellent early bactericidal activity [25] while its use in combination with linezolid and bedaquiline for 6–9 months is currently under study [26].

While not necessarily new, some drugs had gained evidence and proved benefits against TB. Among them, linezolid has been clearly identified in two small randomized clinical trials [27,28] and different meta-analyses as the key drug for XDR-TB regimens [29,30], but frequent, and sometime severe side effects limit its use. Despite the Global Drug Facility is currently offering 600 mg pills at $8 (US), the market price unfortunately still limits its use in most developing countries [31].

Along these years, clofazimine, a drug mainly used for leprosy, has achieved the consideration as a core drug in the MDR-TB 9-month regimens [32] and it is being widely used for MDR-TB and XDR-TB patients with positive results [33]. Clofazimine seems to create instabilities in the bacterial wall that enhance the entry of the other drugs inside of the bacilli, and probably has an untested capacity to reduce the length of the TB treatment [22].

Carbapenens, a wide spectrum β-lactamase group, jointly with clavulanic acid appears to increase chances of a cure to patients presenting with XDR-TB [34]. Again price and injectable formulations reduce its availability for long treatments in most developing countries [31]. In any case, this group merits further evaluation, especially the new drugs with greater half-life allowing daily outpatient intake like ertapenem [35] or the new oral forms like faropenem [36].

New DR-TB regimens

Probably the great advancement under TB regimens was the 9-month regimen for MDR-TB, also known as the Bangladesh regimen [32] that comprises gatifloxacin, clofazimine, ethambutol, and pyrazinamide throughout the treatment period supplemented by prothionamide, kanamycin, and high-dose INH during an intensive phase of a minimum of 4 months. The use of moxifloxacin or gatifloxacin in high doses is the core of the regimen, and their sterilizing capacity seems to be the cause of the reduced length. This regimen has yielded cure rates as high as 85%. Slight variations on this regimen used in West Africa in HIV-negative and HIV-positive patients have delivered similar good results. There is an ongoing multicenter randomized controlled trial (STREAM trial) testing this latter regimen compared to the current standard of 21 months [37].

Brief perspective

Despite the aforementioned advances, DR-TB cure rates remain as low as 50% worldwide. In other words, there are advances that have yet to take effect. What is the reason for this? There are many variables, especially in developing countries where the DR-TB problem is huge, qualified human resources reduced, and overall health systems limited. This ‘50% cure rate’ situation directly correlates with past and persistent lack of funding.

The first step was making visible the invisible. The next step has to be reducing mortality which is mainly among TB-HIV and DR-TB patients. To create this necessary change in developing countries, simple and quick diagnoses need to be accompanied by shorter and user-friendly regimens with predicted and reversible/tractable side effects. The DR-TB dimension is such that task shifting to less specialized health-care workers and de-centralization might be necessary. For that to succeed without creating further resistance, all this knowledge must be shared with health and community care workers on the front lines.

Regarding diagnosis, we believe that the genetic revolution has just started. Research on gene mutations and new diagnostic devices will soon appear. We expect to work with TB virtual-phenotypes over the next decade as is routinely done now in HIV.

In the short run, we believe that if the results of the STREAM trial and the cumulative observational evidence is favorable, the ‘Bangladesh regimen’ will become the new standard MDR-TB regimen. But it is still too long, complex, and toxic. New drugs too will bring hope for salvage regimens while gaining knowledge for shorter and less toxic regimens for susceptible TB. An optimization on the use of old drugs like RIF in high dose, or finding the most useful and less toxic linezolid dose will also have a substantial role to play. The fact of not having three completely new drugs for a full new salvage regimen can be critical. If drugs appear with a lag of more than 5 years, resistance patterns can continue increasing.

Finally, no matter how many advances occur, we can only cure those patients that take their medication. We will not cope with drug resistance unless community systems and political will are implemented to assure adherence, adequate follow-up, and support of patients.

We are certainly better placed in the grid now than 5 years ago and the future looks brighter than ever. But TB still probably remains historically the most neglected infectious disease.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.