“What will it really take to eliminate drug-resistant tuberculosis?”

Summary

Drug resistant tuberculosis (DR-TB) is challenging to diagnose, treat, and prevent, but that is slowly changing. If the world is to drastically reduce the incidence of DR-TB, we must stop creating new drug-resistant TB as an essential first step. The drug-resistant TB epidemic that is ongoing must also be directly addressed. First-line drug resistance must be rapidly detected through universal molecular testing for resistance to at least rifampin and preferably other key drugs at initial TB diagnosis. DR-TB treatment outcomes must also improve dramatically. Effective use of currently-available, new, and repurposed drugs, combined with patient-centered treatment that aids adherence and reduces catastrophic costs, are essential. Innovations within sight, such as short, highly-effective, broadly-indicated regimens, paired with point-of-care drug susceptibility tests, could accelerate progress in treatment outcomes. Preventing or containing resistance to second-line and novel drugs is also critical and will require high-quality systems for diagnosis, regimen selection, and treatment monitoring. Finally, earlier detection and/or prevention of DR-TB is necessary, with particular attention to airborne infection control, case finding, and preventive therapy for contacts of patients with DR-TB. Implementing these strategies can overcome the barrier that DR-TB represents for global TB elimination efforts, and could ultimately make global elimination of DR-TB (fewer than one annual case per million population worldwide) attainable. There is a strong cost-effectiveness case to support pursuing DR-TB elimination, but achieving this goal will require substantial global investment plus political and societal commitment at the national and local levels.

Introduction

The WHO End TB Strategy and the United Nations Sustainable Development Goals set a vision for drastically reducing TB incidence by 2030 and for ultimately eliminating TB as a public health problem.^1,2 Drug resistance presents an obstacle to achieving those goals. The global burden of drug-resistant (DR) TB is imprecisely-known and heterogeneous, but worldwide, an estimated 600,000 people developed multidrug-resistant (MDR, resistant to at least isoniazid and rifampin) or rifampin-resistant (RR, all rifampin resistance irrespective of isoniazid) TB in 2016.³ MDR and RR-TB were also responsible for over 25% of all deaths from antimicrobial-resistant infections.⁴ Across high-burden settings with known trends, incidence of MDR-TB is declining more slowly or increasing more quickly than that of TB overall (Figure 1).³

Figure 1. Observed TB and MDR-TB trends.

The limited number of high burden settings which have serially-collected data on MDR-TB burden all report that MDR cases are declining more slowly or increasing more rapidly than DS-TB incidence, and thus MDR-TB is growing as a proportion of overall TB. Several such countries are observing steady declines, however, in the absolute incidence of MDR-TB.

There are reasons for optimism, however, about the potential to alter the trajectory of DR-TB. Historical factors contributing to today’s DR-TB epidemic can now be overcome by scaling up existing diagnostic and therapeutic strategies. Going forward, improved diagnosis, drugs, and care delivery for DR-TB could help to lower the intensity of DR-TB transmission. Simultaneously, reducing drug-susceptible (DS) TB cases could shrink the pool from which drug resistance develops. Now is an opportunity to change course – and to consider what would be required to achieve DR-TB elimination.

Elimination of DR-TB can be understood both as a component of overall TB elimination and as a goal in its own right. DS- and DR-TB epidemics are intrinsically linked. DR-TB is both an already-entrenched part of the global TB epidemic and a renewed risk each time TB is treated.⁵ Yet most cases of MDR-TB today result from MDR-TB transmission events.^6,7 Therefore, targeted efforts are required even to merely keep DR-TB in check. However, a more proactive and ambitious reframing of goals for combating DR-TB is conceivable. Global TB efforts have begun to focus upon elimination, defined as one incident case per million people per year.⁸ Extending this target to MDR- and RR-TB – which currently number around 80 cases per million per year globally³ – sets an ambitious but achievable target that could unify and motivate both global DR-TB response and TB elimination efforts.

In this article, we consider what would be required to reach this DR-TB elimination target. We present (and summarize in Table 1) a roadmap for how to efficiently approach, and ultimately achieve, global DR-TB elimination.

Table 1:

Summary table of barriers to drug-resistant TB elimination and action steps for addressing them

Barrier to elimination	Description of the barrier	Solutions
Preventing generation of DR-TB
Acquired first-line drug resistance	A fraction of DS-TB patients develop resistance to drugs in their regimen.	Improve quality of DS-TB care (optimal dosing, authentic drugs, patient support, programmatic quality improvement, DST). Pursue multi-faceted efforts to reduce overall TB incidence.
Improving DR-TB diagnosis
Late TB diagnosis	Individuals with DR-TB are often diagnosed with TB after significant transmission (or are never diagnosed).	Improve access to TB screening and evaluation and to rapid, sensitive TB diagnostics (e.g. X-rays, Xpert MTB/RIF). Perform active case finding + DST among DR-TB risk groups, including high-TB-incidence populations and DR-TB contacts.
Under-detected first-line drug resistance	Most TB patients are not tested for drug resistance.	Perform universal DST, at least for rifampin, in all TB patients prior to treatment. Increase availability of rapid DST, including laboratory support and infrastructure including electricity or alternative energy supplies.
Under-detected second-line drug resistance	Many MDR -TB patients have additional drug resistance.	Strengthen laboratories, sample transport, and results-reporting systems for centralized DST. Improve second-line DST options (including both point-of-care molecular assays and whole genome sequencing).
Improving DR-TB treatment
Low regimen efficacy	Critical components of short-course TB therapy are inactive against MDR-TB.	Increase access to newer drugs that can increase regimen efficacy. Monitor DR-TB patients for treatment non-response, and react promptly. Pursue development of shorter, more effective DR-TB and pan-TB regimens.
Inadequate treatment completion	Conventional MDR-TB therapy has ≥18 month duration, significant toxicities, and high rates of attrition.	Develop more tolerable drugs from existing and new drug classes. Use shorter and more tolerable regimens when clinically appropriate. Engage patients in decisions and provide treatment literacy and adherence support throughout treatment. Ensure adequate financial and social support for patients.
Limited treatment access	Logistical and programmatic barriers often prevent or delay DR-TB treatment.	Provide DR-TB care in decentralized ambulatory settings. Cautiously use standardized regimens to facilitate access, while also strengthening second-line DST access, local clinician training, and specialized referral/consultation systems. Pursue development of shorter, all-oral, and more-universal regimens.
Acquired second-line drug resistance	Second-line drug resistance is acquired frequently and makes DR-TB more difficult to cure.	Invest pre-emptively in better DR-TB treatment now. Make quality improvement part of DR-TB treatment programs. Monitor for acquired resistance to new TB drugs.
Preventing propagation of DR-TB
Transmission in public settings	Hospitals in particular can be hotbeds of transmission of undetected or ineffectively-treated DR-TB.	Strengthen airborne infection control in hospitals and other settings where transmission is common.
Transmission to close contacts	Contacts of DR-TB cases often have latent DR-TB infection and a high risk of reactivation.	Monitor close contacts of MDR- and RR-TB patients for development of active TB. Consider preventive second-line antibiotic therapy when latent MDR-TB is likely.
Latent DR-TB reservoir	Elimination DR-TB will require eliminating most DR-TB reactivation.	Pursue more tolerable and easily-administered preventive therapies.
Supporting and funding DR-TB elimination
Complacency	DR-TB moves slowly and affects marginalized populations; political urgency is often lacking.	Advocate for investment commensurate with health burden and public health threat. Advocate for DR-TB care as part of a fundamental human right to health.
High costs of DR-TB care	DR-TB drugs and care delivery consume a disproportionate share of tightly-constrained TB budgets.	Increase overall TB funding. Innovate or adopt lower-cost care models. Integrate DR-TB care into broader health system.
Poverty and weak health systems	Social disadvantage and poor health contribute to TB and DR-TB risk.	Strengthen health and community systems broadly. Reduce poverty and improve access to health care.
Limited epidemiologic, economic and implementation data	Uncertainty about the burden and distribution of DR-TB, and about the costs and efficiency of DR-TB control modalities, limits strategic planning.	Establish globally-representative DR-TB surveillance. Strengthen and modernize DR-TB information systems for disaggregated real time reporting. Assess feasibility and costs of the above interventions in different settings, in order to identify the most efficient path to DR-TB elimination.

Although our current discussion contemplates elimination of MDR- and RR-TB, drug resistance is an evolving concept, and foreseeable advances in drug development are likely to reduce the importance of resistance to rifampin and isoniazid in particular. Still, TB drug resistance will remain an important risk that must be monitored and minimized. As the evolving treatment landscape⁹ alters what definition of “drug resistant” TB is most relevant, principles we outline will continue to apply.

Addressing DS-TB: essential but insufficient

Combating TB overall – more than 90% of which is drug-susceptible – is essential to DR-TB elimination. Treatment of DS-TB can lead to acquired drug resistance by selecting for spontaneously-occurring, resistance-conferring mutations, and effective treatment limits this risk. Programs should treat DS-TB with proven drug regimens (including increasingly considering host characteristics¹⁰ and non-RR/MDR drug-resistance¹¹ as risk factors for poor outcomes), ensure reliable supplies of quality-assured drugs, support patient adherence, implement TB infection control, and make quality improvement a key component of national TB programs.¹² Research toward a shorter duration of DS-TB treatment should likewise be reinforced. Preventive interventions, which lower the number of DS-TB patients requiring treatment, also prevent DR-TB, because they shrink the reservoir from which acquired resistance can develop. Finally, programmatic efforts to improve case detection can reduce transmission of all forms of TB, including DR-TB.

Implementation of current DR-TB guidelines as the next step

Drug resistance must be considered in all patients diagnosed with TB. The prevalence of MDR- or RR-TB among TB patients with no prior treatment is 4.1% globally and exceeds 1% in nearly all high-TB-burden countries.³ WHO guidelines have recommended since 2009 – and now strongly recommend – that TB programs perform routine rapid drug susceptibility testing (DST), to rifampin at a minimum, for everyone diagnosed with TB.¹³ The End TB Strategy recommends universal DST at the time of diagnosis as a key component of patient-centered care,¹ and the 90-(90)-90 targets include identifying and appropriately treating 90% of MDR- and RR-TB cases.¹⁴ WHO additionally recommends patient-centered treatment approaches without mandatory hospitalization, a shorter 9–12 month treatment regimen, and incorporating new drugs under specific conditions.¹³ Guidelines address DR-TB prevention by advocating for high-quality treatment of DS-TB, evaluation of close contacts for co-prevalent DR-TB and possible preventive therapy,¹⁵ and improved infection control for health facilities and congregate settings.¹⁶

While scale-up of these existing policies is unlikely to be sufficient for reaching DR-TB elimination, they represent an important step. Unfortunately, a considerable gap exists between international guidelines and their national-level adoption and implementation. Tight constraints on financing, infrastructure, technology, and expertise can hinder implementation of recommendations. Competing health priorities, uncertainty about how to localize global recommendations, and the inertia of established practice can be important barriers to progress.

On the diagnostic front, progress toward universal DST has been accelerated by Xpert MTB/RIF but remains inadequate.¹⁷ DST coverage remains insufficient among bacteriologically-positive TB patients (just 33% of those newly diagnosed were tested in 2016) and absent among the 43% of TB diagnoses that are bacteriologically unconfirmed.³ DST, when performed, is increasingly limited to rifampin alone.¹¹

Implementation of newer approaches to DR-TB treatment remains similarly limited. In a recent survey of 29 high-TB-burden countries, use of the 9–12 month treatment regimen, bedaquiline, and delamanid were included in the policies of 45% (13), 79% (23), and 62% (18), respectively.¹⁸ Compulsory hospitalization at the start of MDR-TB treatment, which can restrict treatment access and delay treatment initiation,^19,20 was still required by 9 (31%) surveyed countries.¹⁸ Despite success rates above 80% for standard MDR-TB treatment in recent clinical trials²¹ and some national programs,²² the latest global treatment success rate for MDR-TB is 54%.³

As a result, as Figure 2 illustrates, currently fewer than 1 in 4 individuals with MDR- or RR-TB worldwide receive corresponding treatment, and only an estimated 1 in 8 are successfully treated.

Figure 2. Cascade of care for drug-resistant TB worldwide.

The boxes to the left show an estimate of the people at risk to develop either transmitted or acquired rifampin-resistant (RR) or multidrug-resistant (MDR) TB. The orange bar chart shows the people with active MDR- or RR-TB (estimates for 2016, based on aggregation of often-limited country-level data³) who are lost at the stages of TB diagnosis, drug resistance diagnosis, initiation of treatment, and completion of curative treatment.

Role of improved diagnosis

Diagnostic tools

If MDR- and RR-TB are to be eliminated, they must first be detected in a timely fashion. The quickest way to accomplish this with today’s tools is to scale up the Xpert MTB/RIF rapid molecular diagnostic test and the infrastructure to support it. Xpert MTB/RIF, included in the first WHO Essential Diagnostics List, detects rifampin resistance with high accuracy and significantly increases programmatic detection of MDR- and RR-TB when used at the time of TB diagnosis.²³ The new-generation Xpert MTB/RIF Ultra has a higher sensitivity for detecting M. tuberculosis and promises to further increase TB and RR-TB case detection.²⁴

Still, DR-TB elimination will require the expansion of rapid testing for resistance to a growing menu of drugs. Isoniazid monoresistance is a precursor of MDR-TB and a highly prevalent predictor of first-line treatment failure.²⁵ Recognition of second-line drug resistance is also important to ensure successful MDR-TB treatment.²⁶ Development of a scalable rapid molecular test for use in a decentralized setting, including DST for additional key drugs besides rifampin, was deemed a priority by a WHO consensus committee.²⁷ Several next-generation drug susceptibility tests for use at microscopy centers are currently in development, adding DST for such drugs as isoniazid, fluoroquinolones, and aminoglycosides.^28,29 As standardized treatment regimens adopt new drug classes, rapid molecular testing for resistance will need to evolve congruently.

In parallel with scale-up of point-of-care tests, expansion of DST at the centralized lab level is also important. Techniques for centralized DST include existing molecular tests (such as the Hain Genotype MTBDRsl line probe assay, for second-line drug resistance) and phenotypic methods. Eventually centralized DST will incorporate emerging molecular tests (such as the BD Max MDR-TB, Hain Fluorotype MTBDR, and Abbott Realtime MTB assays). DST also may increasingly include whole genome sequencing (WGS), which can theoretically identify all resistance-conferring mutations at once and predict their functional effect. WGS is, for example, considered the best approach for diagnosing resistance to pyrazinamide, a key first-line drug included in a number of second-line regimens. WGS could become the future of DST, but several obstacles must first be overcome in terms of speed (e.g., reducing turnaround time, performing testing on clinical samples directly rather than waiting for culture), accuracy of predicting phenotypic resistance (particularly problematic for certain drugs³⁰), demonstration of improved clinical outcomes, and resource requirements.³¹

Lastly, a diagnostic strategy for DR-TB elimination will require integrated DST solutions across multiple levels of health care provision (Figure 3). Some tests should be optimized for primary care and made readily available at patients’ point of contact within the health system. Other tests are appropriate for centralized settings. Adequate linkages between levels are required, including sample transport and patient referral systems, diagnostic connectivity, and information and communication technologies that can notify patients and physicians of test results and facilitate timely linkages to care.³² Lack of such integration causes large losses during the cascade of care (Figure 2).

Figure 3. Tackling the complexities of DR-TB involves bringing care closer to DR-TB patients, but also developing strong centralized or reference laboratories and ways to link into them when required.

This value chain is illustrated here for diagnostic and laboratories, but similar principles apply for treatment (providing care in decentralized ambulatory settings, with strong consultation or referral systems for those who experience complications or require more expert decision-making or specialized treatment). POC: point-of care; DST: drug susceptibility testing; NAATs: nucleic acid amplification tests

Case finding strategies

Earlier case detection has been recognized as essential for overall TB elimination,³³ and similar principles make enhanced TB case finding vital among people at risk for DR-TB. Many individuals with DR-TB are never diagnosed with TB, or are diagnosed only after a lengthy period of disease. In populations with high DR-TB incidence (including those with an average prevalence of drug-resistance but a high incidence of TB overall), active TB case finding and appropriate clinician awareness – paired with rapid DST – have potential to hasten detection of DR-TB and interrupt transmission.

Systematic screening of populations exposed to DR-TB, such as household contacts, is another important and efficient strategy to enhance DR-TB case-finding. Contacts of patients treated for DR-TB are a readily-identifiable population, who bear a considerable risk of infection and disease. A meta-analysis reported 47% (95% CI: 33–61%) and 8% (6–10%) yield for latent infections and active disease, respectively, at the time of initial contact investigation, although the findings varied considerably between settings.³⁴ Because infected contacts remain at high risk of incident disease, both screening at the time of identification and ongoing surveillance are recommended.³⁵ For contacts determined not to have active TB, preventive therapy should increasingly be considered, as discussed below.

Role of improved DR-TB treatment

Beyond MDR- or RR-TB diagnosis, substantial gaps persist in the access to treatment³⁶ and treatment outcomes. One limitation is current standardized MDR -TB treatment regimens, which are complex to implement, lengthy (typically 18–24 months), toxic, poorly tolerated, poorly effective, and difficult for patients to complete.^37,38 Other barriers that limit access to MDR- and RR-TB treatment include delays in receiving diagnostic results, high costs of second-line drugs, and provision of treatment only in specialized centers. To optimize treatment outcomes for those diagnosed with MDR- or RR-TB, both drug regimen and care delivery aspects of treatment must improve, as detailed below.

New drugs and regimens

On the drug regimen front, improvements in MDR- and RR-TB treatment can be made using drugs that exist today. The inclusion of bedaquiline,^39,40 delamanid,⁴¹ repurposed drugs such as linezolid and clofazimine, or conventional drugs at higher doses⁴² can increase regimen efficacy, and these agents should be made available to patients for whom they are indicated. But because individual drugs will not change the inconvenience and poor tolerability of the conventional regimen that limit treatment availability and completion, their impact on DR-TB transmission and incidence will be limited. The shorter 9–12 month regimen being adopted in some countries can facilitate management and improve adherence for eligible patients.^13,43 However, weaknesses in this shorter regimen – including eligibility restrictions, an injectable component, and preliminary trial results that have not established non-inferiority to the conventional treatment⁴⁴ – are likely to make its role temporary while alternative short regimens remain under investigation.

Achieving a dramatic reduction in DR-TB incidence through enhanced treatment will require – in addition to filling the huge diagnostic gap – a dramatic improvement to existing DR-TB treatment regimens. Treatment must become shorter, simpler to dose, all oral, more effective, and less toxic, according to already described principles.⁴⁵ Existing health systems are treating DS-TB with an 85% global treatment success rate. A similarly-efficacious, 6-month, all-oral regimen could make similar success rates feasible for MDR- and RR-TB. For the near future, hope lies in 6–12 month all-oral regimens being developed specifically for MDR- and RR-TB; such regimens are currently under evaluation in clinical trials (TB-PRACTECAL [clinicaltrials.gov NCT02589782], endTB [ NCT02754765], MDR-END [ NCT02619994], ZeNiX [ NCT03086486]).⁴⁶ Though preliminary, results of a combination of bedaquiline, pretomanid, and linezolid in extensively drug-resistant TB are encouraging. ⁴⁷ Developing less-toxic drugs from these new classes could enhance their usefulness.⁴⁸ On a more distant horizon, a highly-effective, short-course “universal” TB regimen indicated for both DS- and DR-TB could represent a major step towards TB and DR-TB elimination,⁴⁸ although such regimens still carry a number of uncertainties and would likely remain universal for a limited time only.^49,50 Ultimately, a healthy drug development pipeline will be key to eliminating DR-TB.

Access to quality care

While the world waits for better and more affordable treatment regimens, improved treatment access and treatment completion can still allow more people with DR-TB to be cured. Many people with MDR- or RR-TB never initiate treatment, and among those who do, loss to follow-up (typically affecting 15–20% of patients) is the largest barrier to higher success rates.³ Scale up of treatment provision in many high burden settings will require adapting models of care to provide ambulatory treatment at lower (e.g. district and sub-district) levels of the health system. Decentralizing treatment and removing reliance on inpatient admission can improve access, reduce delays, and make treatment more patient-centered,^19,51,52 and has proven feasible across different contexts and countries.^19,51,53,54 To enable this, TB programs will need to routinely implement quality improvement strategies.

In choosing DR-TB treatment regimens, there is currently a tension between ensuring that all patients receive effective regimens (which often requires additional DST and evidence-based treatment individualization for patients with second-line drug resistance) and choosing well-designed standardized approaches that facilitate larger-volume, simplified approaches to treatment. Until regimen and DST development allow treatment to be easily tailored at the point of care, programs that seek to expand treatment coverage must balance individualization and access.⁴⁹ The ideal balance is setting-specific (depending, for example, on epidemiology of second-line drug resistance) and is likely to change over time. Enhanced training and decision support, possibly including broadly-applicable regimen selection algorithms, should be provided to clinicians who make DR-TB treatment decisions. Regardless of regimen, all DR-TB patients should be monitored for treatment response, with efficient and timely systems for referring patients to more-specialized care when required.

In the short term, an unfortunate consequence of enhanced detection of DR-TB will be increased pressure upon TB treatment programs, particularly in resource-limited settings.⁵⁵ Therefore, efforts to enhance case detection must be accompanied by simultaneous strengthening of TB programs. Efforts to re-orient TB programs towards a patient-centered approach will be an important part of this renewed effort. Patient support services – including adherence counselling, treatment literacy, and socio-economic support⁵⁶ – need to be continually emphasized and funded within programs. This is likely to both improve treatment outcomes through improved retention in care, and reduce the negative impacts of treatment upon patients. Fully involving patients in decisions about their treatment is another important aspect of patient-centered care that may increase engagement. Expanded provision of treatment must be accompanied by capacity to effectively monitor treatment, for both treatment response and adverse events. New digital adherence technologies, such as mobile phone and electronic reminder systems, are likely to play an increasing role in efficient adherence support in high and low-income settings.⁵⁷

Minimizing and managing second-line drug resistance

Drug-resistance acquisition occurs even under good treatment conditions with efficacious first-line drugs,⁵⁸ but acquisition of resistance is particularly problematic for second-line drugs due to limited drug efficacy and varied baseline drug-resistance phenotypes.⁵⁹ Globally, 6% of MDR- or RR-TB TB are also resistant to both fluoroquinolones and second-line injectable drugs,³ with much higher rates in some settings where these drugs have been widely used.^60,61 Novel drugs are subject to the same evolutionary pressures.⁶² The antimicrobial pressure of DR-TB treatment scale-up could make incident DR-TB increasingly drug-resistant and difficult to treat. Deliberate steps must be taken to minimize acquisition of second-line drug resistance and prevent its spread.

In the multi-national PETTS cohort study of acquisition of drug resistance during MDR-TB treatment,^26,59 two dominant predictors largely determined successful MDR-TB treatment outcomes: the number of DST-proven effective drugs used for treatment, and the extent of drug resistance prior to treatment. The importance of treating with a larger number of effective drugs is intuitive but highlights benefits of performing second-line DST and tailoring treatment when necessary to ensure effective regimens.⁶³ Regimens that contain ineffective drugs, even when successful, also expose patients to toxicity risk without benefit. There are also critical implications to the finding that resistance worsens outcomes even after accounting for the number of effective drugs prescribed: prompt and effective treatment for DR-TB today, before strains acquire additional resistance or highly-resistant strains spread, will improve DR-TB outcomes in the future and ultimately make elimination more attainable.

The PETTS study also revealed that a TB program’s participation in the Green Light Committee initiative was associated with substantially better treatment outcomes and less acquired resistance.⁵⁹ This effect could best be explained by many program criteria working together, including (a) government commitment, (b) well-functioning management systems, (c) expert clinicians with peer review, (d) quality-assured drugs, (e) a highly-functioning laboratory, (f) adequate inpatient and outpatient care facilities, (g) sound diagnostic and treatment protocols, (h) adequate treatment delivery, (i) management of adverse events, and (j) information systems with standardized periodic reporting.⁶⁴ Unfortunately, stringent requirements can adversely limit access to treatment.⁶⁵ Programs pursuing DR-TB elimination should aim for similar high standards while also expanding access.

Role of prevention

As has been shown for DS-TB,^33,66 DR-TB will not be eliminated unless the large reservoir of latent infection is reduced. An estimated 23% of the world’s population is infected with M. tuberculosis, and three million individuals worldwide are newly infected with isoniazid-resistant TB each year.⁶⁷ While the absolute burden of latent MDR- or RR-TB infection is unknown, indirect evidence (e.g., similar proportion of MDR-TB among adults and children,⁶⁸ high prevalence of MDR-TB among treatment-naïve patients in moderate-burden countries of Eastern Europe⁶⁹) suggests that reactivation of latent MDR-TB is common. If the annual incidence of MDR- or RR-TB is 8 per 100,000³ – and even if only 25% of this incidence (2 per 100,000) reflects reactivation – then 19 of 20 MDR- or RR-TB reactivation events must be prevented to achieve global elimination. Achieving DR-TB elimination will therefore require (a) improved infection control, (b) preventive therapy for both DR-TB and DS-TB, and (c) improved strategies for delivery of preventive interventions at a population level.

Infection Control

Hospitals and other congregate settings can be foci of DR-TB outbreaks,⁷⁰ and health care workers are also at elevated risk for TB, including DR-TB.⁷¹ Frequent delays in effective treatment for DR-TB make measures to prevent nosocomial transmission particularly important.⁷² High-income countries established airborne infection control programs and respiratory isolation units in response to healthcare-associated TB outbreaks in the 1990s, occupational safety legislation, and the SARS epidemic.⁷³ They must now transfer their experience and technology to middle and lower income countries most affected by TB, supporting implementation of protective measures including environmental ventilation, isolation protocols, and respirator masks. Clinical practices must also facilitate prompt diagnosis of coughing patients who could have unrecognized TB.⁷⁴

DR-TB preventive therapy

Because of their high risk of incident DR-TB, contacts of DR-TB patients may be considered not only for DR-TB case finding but also for antibiotic therapy to prevent latent DR-TB infection from developing into active disease. Effectiveness data are currently limited,^75,76 but WHO recently provided a conditional recommendation supporting preventive therapy based on individual risk assessment of contacts of DR-TB patients, while trial results are awaited.¹⁵ Three clinical trials are underway to evaluate the effectiveness of levofloxacin (TB CHAMP [ISRCTN92634082] and V-QUIN [ACTRN12616000215426] Trials) and delamanid (PHOENIX MDR-TB Trial [A5300B/I2003B]) in treating drug-resistant infection. These trials are expected to clarify how to most effectively manage DR-TB contacts and other individuals with likely DR-TB infection.

Need for new preventive tools

While preventive therapy regimens are likely to play an important role for DR-TB contacts, much TB transmission occurs outside of known close contact pairs.⁷⁷ To reduce the reservoir of latent DR-TB to a level sufficient for elimination, we need novel tools – namely a well-tolerated, easily administered, highly effective preventive regimen with activity against MDR-TB. Ongoing efforts to identify effective and tolerable preventive regimens for DR-TB – paired, ideally, with improved diagnostics for identifying those at risk of progression to TB disease – must be prioritized if the goal of eliminating DR-TB is to be attained.

Political commitment to elimination

DR-TB elimination will require bold action and sustained commitment on the part of many, including governments, health systems, investigators, clinicians, and funding bodies. The first ever United Nations High Level Meeting on TB in September 2018 is an opportunity for increased political commitment followed by bold actions.

In 1985, eminent TB clinician Michael Iseman warned that “we are transforming an eminently treatable infection into a life-threatening disease that is exorbitantly expensive to treat.”⁷⁸ The potential cost of complacency remains the same today: each time we fail to cure a patient with DR-TB, or miss an opportunity to prevent DR-TB from developing, we increase human suffering and also increase the work required for DR-TB treatment in the future.

If we are to end the DR-TB epidemic, the path to elimination needs to incorporate large-scale prevention, patient-centered care, engagement of affected communities, and strategic innovation. A globally-representative sentinel surveillance system could aid strategy and priority-setting. To advance the diagnostic and therapeutic pipelines, there may be roles for innovative funding mechanisms and regulatory incentives.⁷⁹ It is also critical that communities at highest risk for DR-TB be given greatest access to new diagnostic tools and medicines⁸⁰– as well as to broader poverty reduction interventions. Broadly-shared social and economic advancement are also likely to reduce all forms of TB⁸¹ and aid in DR-TB elimination.

DR-TB takes a large toll on affected patients, and patient advocacy has an important place on the path toward DR-TB elimination. The TB community can learn from the example of HIV in insisting on health as a human right for patients with DR-TB and in working to make effective interventions available for patients with DR-TB in developing countries.⁸² Ultimately, there is a strong case – explored below – that attainment of DR-TB elimination can be cost-effective. Nevertheless, it will require monetary investment by national health systems, with backing from international funding bodies and technology licensees. Aid to lower-income countries should take a long view, transferring technology and expertise and helping to build sustainable TB programs for a decades-long elimination process.

Economics of DR-TB elimination

Allocating sufficient resources to fund DR-TB elimination remains a challenge despite the increasing array of interventions available. The cost-effectiveness of DST and MDR-TB long-course treatment was established over a decade ago, in a range of low- and middle-income countries.⁸³ In many high-TB-burden countries, fewer than 2% of all notified patients are treated for MDR-TB, yet costly DR-TB management consumes 25% of TB budgets.³ Limited overall TB funding and low health spending have left many programs with the stark choice of developing DR-TB services or treating larger numbers of people with DS-TB. Elimination of DR-TB will therefore require a broader policy commitment at a global level to increase TB funding more generally.

The economic gain from DR-TB elimination is potentially sizeable, in terms of future health system costs as well as wider economic impact. While the primary motivation for investment is disease and mortality burden, DR-TB can also be a particularly devastating disease from a poverty reduction perspective, with catastrophic economic costs at the household level.⁸⁴ Despite these compelling qualitative arguments for benefits of elimination, quantifying the case for the large upfront investment required is problematic. Data are lacking on the costs and cost-effectiveness of emerging DR-TB technologies, and of operational and health system costs of expanding DR-TB service coverage to the levels required for elimination.⁸⁵

Nevertheless, the economic understanding of DR-TB is rapidly evolving. Several interventions described above have demonstrated the potential to improve both the costs and cost-effectiveness of health systems’ DR-TB response. Shortened regimens containing new drugs are potentially cost-saving compared to current approaches.^86,87 Likewise, countries like South Africa that have led the move to decentralize care are now benefitting from large reductions in DR-TB treatment costs.⁸⁸ Wider adoption of new service delivery models that reduce hospitalization or allow remote monitoring of therapy may be pivotal in changing the perception of DR-TB treatment as a costly, infeasible endeavor.

A greater challenge lies in making the investment case for the expanded case detection and improved DST required for DR-TB elimination. Rapid molecular DST for at least rifampin, if implemented correctly, is a key part of a cost-effective TB strategy in many settings, but evidence on costs and cost-effectiveness of scaling up rapid molecular DST is more limited than for new treatment regimens. It also varies considerable between settings.⁸⁹ Yet both the technologies and the evidence base on how to efficiently implement them are rapidly evolving. Increasing use of multi-purpose technologies and shared laboratory platforms, and synergy with wider efforts to address antimicrobial resistance, may help to lower the ‘marginal’ costs of scaling up DR-TB treatment services.

There remains a substantial dearth of data on both costs and cost-effectiveness of different modalities of case detection. Developing efficient service delivery models to reach undetected cases remains one of the most under-researched, yet important areas in economics of TB and DR-TB. Understanding the costs and feasibility of different approaches for reaching latently-infected individuals will be similarly critical to ensure that interventions to address latent MDR-TB are cost-effective. A better understanding of these costs at both the global and country level can help to clarify the economic case and the most cost-effective strategy for reaching DR-TB elimination.

Next Steps

Table 1 summarizes the important obstacles faced in pursuing a goal of DR-TB elimination, and proposes a path forward. Efforts to reduce DS-TB can reduce DR-TB both directly and indirectly – but specific actions targeted to DR-TB are also fundamental. Improving DR-TB case detection is essential and requires DST scale-up and targeted case finding, particularly among contacts of DR-TB patients. Once DR-TB patients are in care, providing prompt, high-quality treatment with effective drug regimens in a patient-centered context can improve treatment success. Regimen design should increasingly incorporate new drug options and clinically-relevant second-line DST results, although limitations in the drugs or diagnostic assays available should not unduly limit access to DR-TB treatment in the short term. For DR-TB prevention, as with TB prevention in general, infection control is essential, and preventive therapy has an important role.

These actions – supported by political commitment, financial investment, and broader socioeconomic and health system development – can achieve large reductions in MDR- and RR-TB. As MDR -TB epidemics and our available tools evolve, ongoing evaluations of cost, feasibility, and impact should guide efficient elimination strategies. However, only research and development will allow dramatic transformation of the DR-TB landscape, for example through highly tolerable novel regimens, corresponding point-of-care DST, and preventive therapy with potential for population-wide reach. If the world commits to such a path, then reaching an elimination threshold for DR-TB could become a major global health accomplishment and (with continued attention to DR prevention) an important milestone on the path toward TB elimination overall.