5 курс / Пульмонология и фтизиатрия / Clinical_Tuberculosis_Friedman_Lloyd_N_,_Dedicoat

WHO Groupinga

Group Ab: Include all three medicines (unless they cannot be used)

Group B: Add both medicines (unless they cannot be used)

Group Cb: Add to complete the regimen and when medicines from Groups A and B cannot be used

10–15 mg/kg daily or 3 times a week is often better tolerated than 16–18 mg/kg per day, and is the practice in South Africa given the high rate of isoniazid-associated hepatoxic and neurotoxic adverse events.7

Addition of alternative and other drugs to the regimen will depend on the laboratory-generated susceptibility profile. Ideally at least five likely effective drugs (minimum four), excluding pyrazinamide and ethambutol, should be used in the regimen. However, the precise number that constitutes what is “optimal” remains controversial and will depend on several factors including the efficacy and potency of the drugs being used in the regimen, size and thickness of cavity walls, and disease extent. The PETTS (Preserving Effective Tuberculosis Treatment Study)162 and the recent patient level meta-analysis involving 12,000 patients from 50 studies suggested that at least five effective drugs were associated with better outcomes.163 Thus, in addition to the core drugs already mentioned, additional drugs can be added depending on the resistance profile to create an optimal MDR-TB regimen.

The duration of treatment is also controversial, and the precise duration of therapy remains unclear.

The traditional duration of MDR-TB therapy has been 18–20 months. In 2016, the WHO recommended a shorter 9–11 month duration of treatment under certain conditions, the most important of which was that eligible patients should not likely be resistant to any component of the proposed regimen (except pyrazinamide).164 This standardized regimen consists of an intensive phase of 4–6 months (depending on the time of sputum smear conversion) that includes amikacin,165 moxifloxacin, clofazimine, prothionamide/ethionamide, high-dose isoniazid, ethambutol, and pyrazinamide. This is followed by a continuation phase of 5 months comprising moxifloxacin, clofazimine, ethambutol, and pyrazinamide.164 The STREAM 1 study, a RCT (randomizedcontrolled trail) that evaluated the shorter course regimen in over 400 patients, demonstrated this regimen to be non-inferior to the longer regimen, though bacteriological outcomes were worse with the shorter regimen (higher rates of treatment failure and relapse), and lost to follow-up was higher with the longer regimen.165 Interestingly, it did demonstrate that very good cure rates ( 78%) could be achieved under research conditions with optimal patient adherence and psychosocial support even when bedaquiline and linezolid were not used. Thus, some programs were using the traditional 18–20-month duration of therapy, some the shorter course regimen, while others (like South Africa) were using both, depending on patient-specific characteristics. More recently, however, the South African National TB Programme took the bold but sensible step of including bedaquiline in 9–12 month regimen given the impact of bedaquiline in reducing mortality in MDRand resistance beyond MDR-TB,166–168 and the excellent culture conversion rate shown in several observational studies.167–170 This regimen currently being used in South Africa (since approximately September 2018) is a 9–11-month regimen containing bedaquiline (instead of the SLID), a later-generation fluoroquinolone (levofloxacin), linezolid for 2–3 months, and other second-line drugs. Results of the performance outcomes of this regimen are awaited.

SLID, with appropriate monitoring, can still be considered in patients with fluoroquinolone-resistant MDR-TB, but where resources permit, a subcutaneous tunneled intravenous catheter

should be inserted. Where this is unavailable, it is recommend that amikacin be given intramuscularly together with a local anesthetic, which seems feasible and does not affect the pharmacokinetics of the drug.171 The use of kanamycin is no longer supported given its lack of association with better outcomes (low quality evidence); the same for capreomycin as it was associated with increased mortality. Hearing loss should be monitored, and it has become apparent that subclinical hearing loss is common in populations in TB-endemic countries because of poor access to health care during childhood years (thus access to regular testing is mandatory if injectables are to be used). SLIDs can be dosed at 3 times a week, where appropriate, to minimize toxicity.

The rate of adverse drug reactions in patients with MDRand resistance beyond MDR-TB is high, and patients need to be carefully monitored (see later). When the adverse event is severe enough, the dose may need to be decreased or the drug may need to be stopped. Clofazimine is well tolerated but may often cause hyperpigmentation (poorly accepted by patients who may surreptitiously not take the drug) and prolong the QT interval. Bedaquiline is associated with QT prolongation, although this occurs in less than 10% of individuals and <1% stop the drug due to QT prolongation.172 Thus, bedaquiline-associated QT prolongation is not a major problem in clinical practice.172,173 When faced with an increased QT interval, it is first important to ensure that there are no other concomitant causative drugs (e.g., amitriptyline, citalopram, diphenhydramine, antipsychotics, etc.), electrolyte abnormalities (e.g., hypocalcemia and hypokalemia, often present in HIV-infected persons with diarrhea and malnutrition), or other factors (interactions or issues that increase bedaquiline concentration or duration of action, and genetic predisposition) causing QT prolongation. Occasionally, stopping other QT prolonging drugs such as clofazimine may be required. Linezolid is a particularly toxic drug and, in our experience, has to be discontinued in approximately one-third of patients.174,175 The main adverse events include anemia, peripheral neuropathy, and optic neuritis. Most of the anemia-related toxicity occurs within the first 3 months. Neurotoxicity is evident at a median of 5–6 months.174–176

Medical management of resistance beyond MDR-TB

The principles used to construct a regimen to manage resistance beyond MDR-TB are the same as those outlined in Table 16.3. In South Africa, the typical resistance beyond MDR-TB backbone used comprises bedaquiline, linezolid and PAS, with the addition of other drugs such as delamanid and the carbapenems, as appropriate, so that likely 4–5 effective drugs are used in the regimen. However, with bedaquiline and clofazimine now being used as frontline drugs in MDR-TB, constructing resistance beyond MDR-TB regimens will become more challenging. Treatment will have to rely on extended DST and individualized treatment. It is likely that such regimens will include delamanid and PAS as a backbone, with the addition of carbapenems, and other agents such as rifabutin where appropriate. Indeed, we recently showed that up to 22% of “XDR-TB” patients were susceptible to rifabutin despite being resistant to rifampicin.118,177 Meropenem together with clavulanic acid (given as Augmentin® in endemic countries)

has recently shown good EBA (early bactericidal activity) against M. tuberculosis. Delamanid may potentially be a useful drug for the treatment of DR-TB especially in settings where a regimen of at least 4–5 effective drugs cannot otherwise be constituted178,179; however, the preliminary results of the phase III trial showed that the primary outcome was not met (although significance was achieved when alternative methods for handling missing cultures were used180). Furthermore, the delamanid phase III trial also failed to meet its long-term (>20 month) efficacy outcomes. The reasons for the lack of delamanid efficacy in that trial remains unclear but may have been related to the dosing schedule used, i.e., once versus twice daily schedule.180 In patients with high grade drug-specific resistance, who are often HIV-infected, management is complex and ideally such patients should be managed by multidisciplinary teams comprising social workers, occupational therapists, psychologists, pulmonologists or infectious disease physicians, adherence supporters, and cardiothoracic surgeons amongst others.

With the increasing use of bedaquiline and linezolid, programmatically incurable treatment failures (have failed bedaqui- line-based regimens) are not infrequently encountered and pose a management problem. This is already a challenging problem in Cape Town and in other centers within South Africa. Managing such patients raises a number of ethical and logistical dilemmas including provision of long-term housing, right to work and live in the community, and access to facilities for palliative care. These have been discussed in detail elsewhere.7 Although the majority of these patients succumb to their disease, some self-cures have

Table 16.5  Recommended principles for the surgical management of MDR and resistance beyond MDR-TB

•Patient selection for surgery and management should be interdisciplinary.

•Candidates include patients with unilateral disease (or apical bilateral disease in selected cases) with adequate lung function who have failed medical treatment.309

•In patients with rifampicin-resistant or MDR-TB, elective partial lung resection (lobectomy or wedge resection) was associated with improved treatment success.

•Surgical intervention may be appropriate in patients at high risk of relapse or failure despite response to therapy (e.g., resistance beyond MDR-TB or programmatically incurable TB).309

•Facilities for surgical lung resection are limited and often inaccessible.

•PET-CT may be useful for clarifying the significance of contralateral disease and may have prognostic significance but its role in this context requires validation.310,311

•It is critical that surgery be accompanied by an effective rescue regimen otherwise outcomes are suboptimal.

•The optimal duration of therapy post resection remains unclear.

•Surgery should be performed at a center with relevant experience.

Source: Adapted with permission from Dheda K. Lancet, 2016; Dheda K.

Lancet Resp Med, 2017.

Abbreviations: MDR-TB, multidrug-resistant TB; XDR-TB, extensively drugresistant TB (likely to be redefined soon).

been documented. Indeed, in the pre-chemotherapeutic era, about 15%–20% of patients self-cured their TB.181

The surgical management of MDR and resistance beyond MDR-TB is discussed later, however, when surgery is not an option (unfit for surgery or patient refusal) other experimental options may include the use of one-way valves for medical lung volume reduction.182 There have been several case reports of the successful use of valves, though the valves are expensive, access is limited, and there are major infection control issues that need to be managed. A number of interesting research approaches are currently being pursued, including adjunct inhaled antibiotics, efflux pump inhibitors, therapeutic vaccines, host-directed therapies, and the use repurposed drugs including minocycline and ceftazidime-avibactam.183,184

Surgical management of DR-TB

The majority of patients with MDR-TB, as already outlined, can be cured with medical treatment alone, provided that medicines are available to design a DST-guided treatment regimen of at least five likely effective drugs. However, patients may benefit from additional surgical therapy depending on the physical status of a patient, the availability of drugs, and the extent of the disease (see Table 16.5).

The decision for a thoracosurgical intervention should be made by a multidisciplinary team of experts and the procedure should be performed in a center with experience in MDR-TB thoracic surgery.185 Surgery should be considered in patients with localized pulmonary disease that cannot be cured by medical treatment alone (e.g., non-culture conversion after 6 months of adequate medical treatment, especially when there are large cavities) or when there are life-threatening complications, e.g., pulmonary hemorrhage, non-resolving pleural empyema, or extensive necrosis. The best treatment outcomes are achieved with partial unilateral lung resections though this likely reflects a selection bias.186 Patients considered for pneumonectomy must be carefully selected. A recent meta-analysis on the role of surgery for patients with MDR-TB found no overall benefit of extensive surgical procedures though there were many confounders.186

Potential contraindications for surgical intervention include extensive fibrotic lung disease, bilateral cavitating disease, poor cardiopulmonary function, and endobronchial TB.185 HIV coinfection should not be a contraindication for surgery, however, these patients should receive effective antiretroviral therapy (ideally, they should have undetectable viral replication). In addition to microbiological evaluation, preoperative assessment should ideally include spirometry, chest computed tomography imaging, a ventilation-perfusion scan, diffusion capacity testing, and an echocardiography (if indicated).

The optimal timing for surgery is after culture conversion so that the risk for bronchial stump breakdown is diminished. However, this is a theoretical concern and when culture conversion cannot be achieved by medical treatment, surgical treatment should not be delayed. Patients undergoing elective lung resection should improve their physical fitness prior to and post-surgery using physioand respiratory therapy.

The WHO suggests that patients with MDR-TB who undergo pulmonary surgical therapy need postsurgical medical treatment.185 It remains unclear if this is also the case in patients with

very localized disease who undergo complete surgical resection of a lesion, though intuitively it should be the case. Recent data from the University of Cape Town suggests that surgical outcomes are poor unless accompanied by effective medical therapy (K Dheda; personal communication). The duration and intensity of post-sur- gery medical treatment to achieve relapse-free cure can be highly variable.187,188 General recommendations can only be provided with a large degree of uncertainty.

Management in special situations

MANAGEMENT OF DR-TB IN PATIENTS COINFECTED WITH HIV

Management of DR-TB in the setting of HIV-coinfection is challenging and associated with high mortality. This may be attributed to the potential for shared toxicity between TB and HIV treatment, the presence of HIV-related end-organ disease, pharmacokinetic drug-drug interactions, and immune reconstitution inflammatory syndrome (IRIS).189

Antiretroviral therapy (ART) should be initiated within 8 weeks of starting effective MDR-TB treatment irrespective of CD4+ count.190 Patients with CD4+ counts <50 cells/mm3 should initiate antiretrovirals (ARVs) within 2 weeks of starting MDR-TB treatment as is the case for DS-TB treatment,191–193 unless they are suspected to have TB meningitis, in which case the initiation of ARVs should be deferred by 6–8 weeks due to the risk of developing potentially fatal CNS IRIS (central nervous system immune reconstitution inflammatory syndrome).194,195 The WHO has recently endorsed the use of dolutegravir as part of a first-line ART regimen.196 This agent is not only more effective and better tolerated than previous ARVs but is also expected to be safe for coadministration with newer anti-TB agents such as bedaquiline and delamanid.197,198

New and repurposed drugs used in the treatment of MDR-TB and resistance beyond MDR-TB such as bedaquiline, linezolid, and delamanid have changed the face of MDR-TB treatment; however, significant adverse event profiles require that these agents be used with caution. This is particularly important in settings of high HIV coinfection where the potential for drug interactions is significant (Table 16.6298 summarizes the shared toxicity between anti-TB therapy and ARVs).

MANAGEMENT OF DR-TB IN PREGNANCY

TB in pregnancy is associated with poor outcomes, including an increased risk of preterm birth, low birth weight, intrauterine growth restriction, and perinatal death.199,200 Prevalence estimates for TB in pregnancy and in the postpartum period range from 0.06% to 7.2% and are as high as 11% in HIV coinfected patients.201–203 This high prevalence may be attributed to the reduced ratio of T-helper 1 to T-helper 2 cells which predisposes pregnant women to acquire or reactivate TB.204

Some women may choose to terminate a pregnancy due to the potential teratogenic effects of anti-TB therapy.205,206 All pregnant women should be started on treatment as soon as possible. However, the decision to initiate treatment for DR-TB and the construction of a DR-TB regimen must consider the gestational age of the fetus, and should weigh the risks of the teratogenicity

against potential benefit to the mother.207 The teratogenic effects of anti-tuberculous treatment mainly occur during the first trimester. Therefore, treatment may be deferred until the second trimester in selected cases where the clinical condition of the mother is stable and where there is minimal radiological disease. This strategy, however, must be accompanied by close clinical follow-up as DR-TB in pregnancy, especially in the context of HIV coinfection, can have an accelerated course.208,209 Mothers, especially if smear positive, should discontinue breastfeeding if possible, so as to limit proximity to the infant.

Aminoglycosides, specifically amikacin and kanamycin, are FDA class D agents. These should be excluded from TB treatment regimens during pregnancy because of the risk of ototoxicity and fetal malformation, especially within the first 20 weeks of gestation. Bedaquiline may be used instead of SLID as it is likely safer (FDA pregnancy risk category B) and animal reproduction studies have not demonstrated risk to the fetus.210,211 Delamanid, however, should not be used in pregnancy until more safety data become available since animals studies have demonstrated potential teratogenic effects.212 Both bedaquiline and delamanid are excreted in breast milk in animal studies and therefore, the decision to discontinue the drug or nursing should be taken within the clinical context. Ethionamide is generally avoided as it can increase the risk of nausea and vomiting associated with pregnancy. This drug may be reintroduced after delivery if needed to strengthen the regimen in the immediate postpartum period.

Last, it is critically important to offer individualized, long term, and effective contraception (e.g., medroxyprogesterone or an intrauterine contraceptive device) to all women of childbearing age who are receiving treatment for DR-TB considering the toxic effects of MDR-TB drugs to both the expectant mother and the fetus.

MANAGEMENT OF DR-TB IN PATIENTS WITH RENAL IMPAIRMENT

Factors contributing to the development of renal dysfunction, such as diarrhea and dehydration, should be addressed. Diuretic use and concomitant administration of other nephrotoxins should be rationalized.213 The underlying cause of renal dysfunction may be due to a concomitant medical condition (e.g., hypertension, diabetes) or due to toxicity attributable to ARVs (e.g., tenofovir) and/or anti-tuberculous therapy (e.g., aminoglycoside). The risks of iatrogenic nephrotoxicity may be greater due to the background prevalence of HIV-associated nephropathy (HIVAN) in Africa.

The use of tenofovir and/or aminoglycoside should be avoided in such patients, especially if the patients have advanced HIV215,216 with proteinuria.215,217

The WHO-recommended dosage (and dosing interval) for various anti-TB drugs is based according to the patient’s creatinine clearance and the modality of dialysis.207 In general, all nephrotoxic agents should be discontinued. Bedaquiline should be used in the setting of aminoglycoside-associated nephrotoxicity.

MANAGEMENT OF DR-TB IN PATIENTS WITH LIVER DYSFUNCTION

Patients with significant chronic liver disease should not receive pyrazinamide. Ethionamide, prothionamide, and PAS can also be

hepatotoxic while the fluoroquinolones are rarely implicated in hepatitis. Essentially, all second-line drugs may be used in chronic stable liver disease, but close monitoring of liver enzymes is mandatory and significant deterioration in liver function should trigger immediate withdrawal of the offending drug. The source of other causes of liver dysfunction, including viral hepatitis and alcohol consumption, should be addressed and treated to prevent further complications during treatment. A combination of four non-hepatotoxic drugs should ideally be used when formulating a regimen in patients with chronic liver dysfunction, including a fluoroquinolone, to ensure the efficacy of the regimen.207

Anti-TB treatment should be deferred until the hepatitis has stabilized in cases of acute hepatitis. Chronic hepatitis B infection is considered a risk factor for hepatotoxicity218 in patients receiving TB treatment, especially if they are “e” antigen positive.219 If treatment for hepatitis B infection is indicated, ART should be initiated with the combination of at least two agents active against hepatitis B, e.g., tenofovir and emtricitabine or lamivudine.220,221 Entecavir may be used as a substitute to tenofovir in patients with renal dysfunction (dose adjustment may be required).221 Drug interactions and overlapping toxicities with MDR-TB agents must be considered in HIV/HCV coinfection.220

MANAGEMENT OF DR-TB IN PATIENTS WITH DIABETES MELLITUS

Diabetes increases the risk of primary infection with MDR-TB and is associated with delayed sputum conversion.222,223 Diabetes mellitus may also play a role in the development of DR-TB.224,225 HbA1c may underestimate glycemic control (due to decreased red blood cell life span) in TB/HIV coinfected patients.226

Metformin may exaggerate gastrointestinal side effects when coadministered with anti-tuberculous agents such as ethionamide, PAS, and clofazimine, and can rarely cause lactic acidosis.227 Caution is advised when using nephrotoxic agents and neurotoxic agents in patients with established diabetes. QTc monitoring is advised when using hypoglycemic agents such as sulphonylureas and glinides concurrently with bedaquiline and/ or delamanid.228 Furthermore, caution is also advised when using bedaquiline concurrently with potentially hepatotoxic antidiabetic agents such as thiazolidinediones.229

The management principles of DR-TB in patients with diabetes remain similar to nondiabetic patients. However, this may need reconsideration in view of the increased treatment failure rates seen in patients with uncontrolled diabetes.230,231 Aggressive treatment is recommended for patients with uncontrolled diabetes232 since these patients have increased rates of relapse and recur- rence.233–235 TB clinicians should leverage more frequent patient contact to counsel patients and optimize glycemic control.236

MANAGEMENT OF DR-TB IN THE INTENSIVE CARE UNIT

TB is frequently diagnosed in the intensive care unit (ICU) in patients presenting with or without a respiratory diagnosis.237 The management of patients with DR-TB in ICU is complicated by pharmacokinetic concerns such as poor gastric absorption, high rates of organ dysfunction, and drug toxicity. Furthermore, concomitant renal failure is a common occurrence, which precludes

the use of aminoglycosides and impacts use of various anti-TB agents. Therapeutic drug monitoring (TDM) may be a valuable tool to advise on the timely adjustment of drug therapy.238,239 However, TDM for second-line agents such as linezolid, fluoroquinolones, and injectable drugs is expensive and not widely available. Utilization of dried blood spots (DBS) for linezolid and fluoroquinolones are available and can overcome some of the logistical challenges of performing TDM.240,241

MANAGEMENT OF MDR-TB IN CHILDREN

This recently has been covered in detail by the same authors elsewhere,6 and by others in Chapter 18.

Response to therapy

The goal of anti-TB drug therapy is relapse-free cure by the eradication of M. tuberculosis in the human host. In routine clinical practice the effect of therapy is ascertained by sequential examination of sputum for the presence of acid-fast bacilli and viability of M. tuberculosis by mycobacterial cultures. When compared to patients with drug-susceptible TB, sputum smear microscopy and culture conversion is delayed in patients with MDR-TB on conventional regimens. Ongoing cigarette smoking further delays responses to anti-TB therapy; thus, smoking cessation is especially important for patients with MDR-TB. In a recent multicenter cohort of patients with non-MDR-TB and MDR-TB, the median (interquartile range) time to smear microscopy conversion was 19 days (10–32 days) and 32 days (17–67 days), and to culture conversion was 31 days (14–56 days) and 39 days (6–85 days), respectively. At 2 months of effective treatment, 90% and 78% of non-MDR-TB patients and MDR-TB patients achieved sputum microscopy conversion, and 67% and 61% of non-MDR-TB patients and MDR-TB patients achieved sputum culture conversion.242 How long (from the initiation of treatment) should patients with MDR-TB observe infection control precautions (e.g., be isolated from the general public and the work place by remaining at home or in hospital if appropriate)? This remains unclear and contentious, and will depend on a number of factors including microbiological burden, presence of cavitation, disease extent and severity, HIV status, strain type, and most importantly the number and bactericidal activity of effective drugs used in the regimen. In situations where there are public health implications, and in patients likely to be more infectious, our policy is to confirm culture negativity before infection control precautions are rescinded (often this may occur 3–4 months into therapy when culture negative results become available). With modern regimens containing group A drugs, the time to culture negativity is likely to be shorter.

Ideally, sputum smear microscopy and cultures should be performed at least once every 2 weeks until culture conversion has been achieved (some centers perform weekly examinations) and thereafter on a monthly basis until the end of therapy (the reality in endemic countries is that only monthly sputum culture testing is performed). The kinetics of quantitative grading of the sputum bacillary load (Table 16.7) and the time to positivity of M. tuberculosis cultures are very good indicators of treatment responses.243 A positive sputum culture status by the end of 6 months of therapy should be considered as failure of MDR-TB therapy.244

Table 16.7  Quantitative assessment of sputum specimens using microscopy312

+4–10 in 100 fields (100 fields examined)

++1–10 in 10 fields (100 fields examined)

+++1–10 per field of vision (50 fields examined)

++++>10 per field of vision (20 fields examined)

While sputum microscopy and culture are suitable markers for the monitoring of the early phase of the treatment, other markers are needed for the later phase of the treatment, when bacteria cannot be detected from sputum specimens anymore.245 Clinical and radiological scores have been proposed to monitor treatment responses in patients with MDR-TB, but these scores have not been validated as markers of cure or treatment failure thus far.242 A biomarker from the blood, urine, or exhaled breath that can easily be measured, and that provides early indication of treatment failure or relapse-free cure, is currently not available. Such a marker would revolutionize the clinical management of drugsusceptible TB and DR-TB.245

There is an ongoing debate about how long patients should be considered infectious on DST-guided antimycobacterial therapy. While infectiousness declines rapidly in response to adequate therapy,246 there is substantial concern for public health when discharging patients with MDR-TB from a hospital into the community when acid-fast bacilli are still detectable by sputum microscopy. In some countries, negative M. tuberculosis cultures are even required prior to hospital discharge of MDR-TB patients.247

PERSON-CENTERED CARE FOR DR-TB: HUMAN RIGHTS, TREATMENT SUPPORT, AND PALLIATIVE CARE

With the global goal of TB elimination, greater emphasis has been placed on providing services and care that focus on the unique and individual needs of those who are living with DR-TB. In fact, the first pillar of the WHO’s “End TB” strategy is to provide “integrated, patient-centered care and prevention.” Given that current TB services are structured in a way that prioritizes the needs of providers and programs, a truly person-centered model of care would be a radical shift in the field. In order to move from talking about such care to practicing some care, several actions need to be taken, including focusing on the rights of persons affected by TB, offering optimal treatment support, and working to alleviate suffering throughout the spectrum of care.

Rights-based approaches to DR-TB

In the past, TB programs have focused on a “public health” approach to TB control, where the emphasis was placed on identifying the most infectious persons living with TB—those felt to be driving transmission—diagnosing them with simplified tools, and treating them with “universal”/standardized regimens.248

While it could be argued that this approach has resulted in tens of millions of people being diagnosed and successfully treated for TB, it is equally true that under this strategy, TB has once again become the leading infectious killer of adults, drug resistance has become global phenomenon, and little progress has been made in bending the pandemic curve.249

By contrast, a human rights-based approach focuses on preventing, diagnosing, and treating all persons with TB in a way that maximizes their chance of returning to a healthy and productive life.250 This type of approach is essential for people affected by DR-TB who currently have almost no access to preventive treatment of infection, are misdiagnosed using conventional TB tools such as smear microscopy, and who are offered long and toxic treatment regimens that include drugs to which the mycobacteria may be resistant, and exclude effective drugs that could increase their chance of being cured. Continuing to offer minimal services violates the right to health clause in the United Nations Universal Declaration of Human Rights (article 25).251 Person-centered care for DR-TB must also be built on the right to benefit from scientific progress, which would include universal and timely access to novel diagnostics and therapeutics, something which is clearly lacking in DR-TB today.252

Compassionate treatment support for

DR-TB

Persons living with DR-TB face myriad challenges, and often their health issues are further complicated by pressing socioeconomic problems as well. These issues, including poverty, lack of transportation, and malnutrition have been well documented and are often compounded when DR-TB is diagnosed, since it causes catastrophic expenditures for individuals, families, and communities.253 In spite of the compelling evidence about the myriad barriers to accessing diagnostic and treatment services,254 current approaches to supporting adherence to DR-TB treatment focus largely on directly observed therapy, prolonged hospitalization, and minimalistic educational approaches. In fact, there seems to be a “blame-based” approach to adherence support255 when it comes to DR-TB, even though a significant amount of DR-TB comes from primary transmission, inadequate drug dosing, and health systems errors.256 For authentic person-centered care to be achieved, persons living with DR-TB should be offered treatment literacy, financial, nutritional, and transportation support, and flexible approaches to verifying adherence. Since the toxic nature of DR-TB treatment may be a key factor in nonadherence, persons should be offered regimens that minimize the risk of adverse events—including the use of injectable-free regimens.257

Palliative care to alleviate suffering

Discussions about palliative care in DR-TB often mistakenly focus on end-of-life issues. However, palliative services are aimed at relieving suffering—both physical and psychological—that can occur during the full spectrum of DR-TB care, including after completion of treatment. Because people with DR-TB face significant discrimination and stigma, it has been proposed that in addition to offering medical interventions to decrease pain, reduce air hunger,

improve the work of breathing, and decrease adverse events, counseling and psychological support should also be offered.258

There will be some people living with DR-TB who are not able to achieve cure and will require end-of-life support. It is important that all efforts at cure—including the use of newer agents— are exhausted prior to declaring that a person has fatal DR-TB. It is also imperative that TB programs continue to engage with these individuals to ensure they can still meaningfully engage with others while minimizing the risk of transmission. Counseling support should also be provided as well as planning to help household and family members after the person succumbs to the disease.259

RESEARCH PRIORITIES AND

CONCLUSION

There are a number of research priorities with regard to DR-TB, and these, together with timelines and barriers to achievement, have recently been covered in detail elsewhere.7 However, four of the most important research priorities include: (i) development and evaluation of an effective TB vaccine; (ii) undertaking clinical trials to measure the effect of active case finding on individual treatment outcomes and transmission, (iii) improving knowledge about genetic predictors of resistance to the key first-line and second-line drugs, and develop DNA extraction and sequencing methodology suitable for routine use in a diagnostic laboratory, and (iv) clinical trials to evaluate the safety, optimal dosing, duration, efficacy and combinations of new and repurposed drugs. The elephant in the room remains the development of active case-finding strategies for the diagnosis of DR-TB. With current passive case-finding approaches, a DR-TB patient has already infected 10–15 other individuals and thus, diagnosis and treatment has limited impact on curtailing the burden of disease. Active case-finding strategies may include contact tracing, screening in congregate settings such as prisons, and mobile teams that go out into TB hot spots to find cases of DR-TB. We have recently shown that such an approach using a mobile van is feasible139 and have extended this to a smaller scalable mini clinic concept using a low-cost vehicle manned by 2–3 health-care workers.

DR-TB still poses a major threat to TB control and has a high mortality (30%–60%), which is worse than most cancers and is associated with unsustainable costs. Recent news that the price of bedaquiline has been reduced to $400 per treatment course is welcomed.260 However, how do we effectively tackle the complex problem of MDRand resistance beyond MDR-TB? This will require a creative and committed multi-prong approach. Prevention is always better than cure and therefore, the first major step must be to prevent TB in the first place, and also to address its major drivers including poverty and overcrowding, malnutrition, and tobacco smoking.6,7,116 An effective vaccine would go a long way to massively reducing TB burden over a relatively short period of time. Addressing such issues, including global economic transformation and reducing war and conflicts, together with developing an effective vaccine, will take many decades. In the meanwhile, we need to conserve existing drugs through robust and wellfunctioning health-care systems, well-trained health-care workers, correct dosing of drugs, ensuring that patients adhere to their

therapy, practicing antibiotic stewardship, and by prioritizing and funding innovative research (e.g., optimal drug dosing, the use of adjunct inhaled antibiotics, the use of efflux pump inhibitors, the development of more accurate diagnostics that will allow the initiation of fully individualized regimens).

Other major priority areas include optimal treatment of DR-TB in children, the prioritization of optimal ART regimens, TDM, and management of DR-TB in special populations including pregnancy, HIV-infected persons, those with organ dysfunction, and in the critically ill. However, controlling MDR-TB, and TB as a whole, will only be possible with massive investment of resources, political will, and the eradication of poverty, overcrowding, wars and conflicts, developing universal access to health care, and a reorganized global economic system. There also needs to be a change in the current concept of leadership to one endorsing a global mindset of brotherhood and empathy, otherwise other challenges such as global warming, pollution, and destruction of the environment will wipe out mankind way before TB does.

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