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MDR Tuberculosis Treatment: History
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Subjects: Allergy
Contributor: Aznar Maria Luisa

Multidrug-resistant (MDR) tuberculosis (TB), resistant to isoniazid and rifampicin, continues to be one of the most important threats to controlling the TB epidemic. There have been promising pharmacological advances in the paradigm of MDR TB treatment: new and repurposed drugs have shown excellent bactericidal and sterilizing activity against Mycobacterium tuberculosis and several all-oral short regimens to treat MDR TB have shown promising results. 

  • tuberculosis
  • MDR
  • treatment

1. Introduction

Tuberculosis (TB) continues to be one of the 10 main causes of death in the world, being, since 2015 and until the COVID-19 pandemic, the leading cause of death from a single infectious agent (ranking above HIV/AIDS), responsible for 1.3 million deaths among people not infected with human immunodeficiency virus (HIV) and an additional 214,000 deaths among HIV-infected people [1]. Although there has been a decrease in TB incidence and mortality in recent years, we are still far from the global TB targets proposed by the WHO in its “End TB” strategy launched in 2015 that aims to reduce the absolute number of TB deaths by 95% and the absolute number of new cases TB by 90% by 2035 [2]. The appearance of Mycobacterium tuberculosis (MTB) strains resistant to the most effective drugs is one of the main problems that contribute to the slow decline in TB cases. Multidrug-resistant TB (MDR TB), defined as TB caused by MTB bacilli resistant to rifampicin (RIF) and isoniazid (INH), represents a major threat to global TB control. From a surveillance perspective, data on MDR TB are aggregated with RIF resistant TB (RR-TB), since many settings rely on molecular methods to test RIF sensitivity, which is a subrogate marker of resistance to RIF and INH. Globally, in 2020, 132,222 cases of MDR/RR-TB were documented, and only one out of three cases were enrolled into an adequate treatment program, and only 59% of those treatments were completed. However, the relapse rate in real-world practice is commonly missing, making it difficult to calculate the size of the problem [1]. Hence, there are still important barriers regarding access to diagnostic tests and adequate treatment.
Until 2016, MDR TB treatment was based on an injectable drug plus a fluoroquinolone (moxifloxacin, levofloxacin, or gatifloxacin) with a duration of 18–20 months or longer [3]. In 2016, the WHO treatment guidelines for MDR TB recommended for the first time the use of a short treatment regimen in selected patients, based on the results of several published studies that included cohorts of MDR TB patients treated with regimens with a duration between 9 and 12 months [4][5][6][7]. Despite the incorporation of these abbreviated schemes, the overall success of MDR TB treatment remained far from the 2035 milestones [2]. Moreover, the treatment regimen includes supplementation with an injectable drug and high-dose INH, responsible for a high proportion of side effects including hearing and renal impairment.

2. Current Insights

In spite of the current revolution in MDR TB management strategies, including the diagnosis of molecular resistances and the tailored all-oral short regimens founded in an ever-growing body of evidence, there are several caveats that still make MDR TB a public health concern and an unsolved medical need.
First, as it can be inferred from the manuscript, there are several possible combinations of drugs and durations in the clinical guidelines with no clear preference for any of them. Because of its complexity, the composition and follow-up adaptations of the treatment regimens often needs a team of experts (“TB Consilium”), which is not available everywhere and thus makes the idea of a decentralized care for MDR TB patients quite a challenge. Additionally, some of the recommended regimens and durations were randomly selected, and optimizations should carefully be adopted based on the characteristics of the patients. For example, in the current guidelines all patients are recommended the same duration regardless the burden of diseases and the early response to the treatment; and the short MDR TB regimen includes drugs that have less in vitro and in vivo efficacy than drugs from the A group. Other aspects are the use of drugs not included in group A in the short MDR TB regimens or the use of high-dose INH even in the presence of high-level resistance. Additionally, BDQ and DLM have been used for longer periods than the approved 6 months, and based on their efficacy data and safety profile, recommendations should extend their use beyond 6 months. All these considerations highlight the need for a tailored treatment for the patients with MDR TB and the need to gather real world data to answer these burning questions. Hopefully, this research can help clinicians to understand the peculiarities of the main compounds that are in use for MDR TB. Such guidance should not be understood as a fixed rule, but rather general concepts must guide an adaptive way of thinking.
This complexity offers some opportunities. As new drugs and regimens need supporting evidence, the research needed to obtain such evidence is the perfect place to involve relevant stakeholders together [8]. Community and patients must work with clinicians, researchers, industry representatives, and regulators to build strong networks that accelerate drug and regimen development in a way that is relevant and accepted by its final users [9]. As for many other conditions, TB research can be the opportunity to build and strengthen research and clinical capacities in low-income settings, increasing the quality standards of healthcare for those that are most affected by this disease [10].
The emergence of new, highly effective regimens may open a new way around RIF and INH resistance. Within a few years, we may see the first pan-TB regimen trials, aiming for a unique solution for both MDR and Ds-TB [11]. This will have the advantage of an easier operational implementation [12]. However, we must recall that the classic exposure was once a “pan-TB” regimen and that new first-line treatment may lead to new profiles of TB resistances [13].
Development and implementation require resources, both human and material. In many settings, healthcare personnel are so overwhelmed by daily duties that changes are introduced at a very slow pace [14][15]. The apparent increase in MDR TB incidence that has been reported after the implementation of Xpert MDR® is due to the detection of more cases that shortly before were treated with first-line drugs empirically, hindering the control of the TB pandemic and farming resistant strains [16][17]. New diagnostic tests in TB with an evidence-based benefit in TB management should be rapidly adopted, ensuring that resources and capacity building are ready since they are as important as having the diagnostic test equipment and fungibles. Drug availability is another concern. Global efforts to ensure drug availability in resource-limited settings help with this problem, but sometimes generate disparity between sites. For example, whilst BDQ is widely available in resource-limited settings, [18], it is not easily available in Europe. A global effort to ensure TB drug supplies should be done and lead coordinately by the WHO with rapid roll out of new drugs after a careful evaluation of the risk-benefit trade-off.
Patients with TB often suffer isolation and stigma, but this is by far more patent in patients with MDR TB. Some of the treatments have visible signs of their use (e.g., skin depigmentation with CFZ) [19][20][21]. This causes havoc amongst those with a weak social and familiar support, which may result in poor drug adherence leading to resistance amplification and community expansion. As new drugs will be marketed in the coming years, old implementation problems need to be approached with innovative solutions. Current guidelines recommend that TB care is delivered by multidisciplinary teams with social workers and psychologists encompassing all aspects of the patient with TB.
Finally, in many settings, a subacute disease with social implications such as TB has economic consequences for the household as a unit. One of the EndTB pillars is the elimination of catastrophic costs for those who suffer from TB. These costs are defined as both direct (what the family needs to pay for) and indirect (how much the household has not earned due to the disease) [22]. According to the WHO 2020 global report, about 45% of households suffer catastrophic costs, but the proportion increases to near 80% for the MDR TB subgroup [1]. Long, complex, and toxic treatments increase the costs for the patients and their families and thus make it difficult for them to complete the entire treatment. Again, to fight TB we need more than novel and effective drugs, we need to cover of the problems that the patient with TB suffering, including, among others, stigma, malnutrition, financial difficulties, and substance abuse.

3. Conclusions

Significant changes have occurred in MDR TB treatment recently. There are new and repurposed drugs with good bactericidal and sterilizing activity and several all-oral short regimens have appeared showing promising results. The availability of rapid and sensitive molecular tools to diagnose drug resistance that compose these new regimens will be essential to treat patients with the best combination and avoid resistance emergence. Patients with MDR TB benefit from close monitoring and expert broad knowledge in TB drug follow up, since a drug regimen is usually modified during treatment due to the toxicity or phenotypic drug sensitivity test.

This entry is adapted from the peer-reviewed paper 10.3390/medicina58020188

References

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