5 курс / Пульмонология и фтизиатрия / Clinical_Tuberculosis_Friedman_Lloyd_N_,_Dedicoat

Introduction

Part I: The cases

Part II: The approach

Conclusions

References

INTRODUCTION

Tuberculosis (TB) has been a curable disease since the 1950s. In the more than six decades since then, knowledge has been amassed about how to ameliorate its social causes, prevent its transmission, and treat both its clinical and quiescent forms.1,2 In many highincome settings, this knowledge has been used with great success. Elsewhere, this is far from the case: more than 4,000 people die from this curable and preventable airborne disease each day, mostly in low-income and middle-income settings.3 Distressed by the status quo, in 2012 more than 500 scientists, policy makers, and advocates from around the world signed the Zero TB Declaration, which called for “a new global attitude” in the fight against TB, and argued that, with the right set of interventions, the planet could move rapidly toward zero deaths from TB.4

Although TB incidence has declined over the past 25 years, it has done so at a glacial pace of approximately 1.5% annually.5 At this rate, it will take another two centuries to eliminate the disease. This reality reflects the limited set of interventions recommended in the last three decades for, and implemented in, low-income and middle-income settings—a shadow of the comprehensive set of strategies that has brought the TB epidemic to heel in other places.1,2 Rather than aggressively finding all cases of TB, preventing the disease in those at highest risk, and focusing on populations and places of highest transmission, most low-income and middle-income settings have focused narrowly on the diagnosis and treatment of those people sick with TB who manage to access care on their own. An over-reliance on standardized treatment and sputum smear microscopy—a low-sensitivity visual diagnostic test that cannot determine drug resistance—has sidelined not only individuals whose illness is characterized by a lower bacillary load, such as children and individuals with HIV, but also those with extrapulmonary forms or drug-resistant TB.6 Early detection and

401

402

404

408

408

treatment of both active disease and quiescent (the so-called latent) infection, along with efforts to control transmission in health care and congregate settings, have been recommended belatedly but have yet to be widely scaled up.7 Much of the policy framing to date has been driven by concerns over cost, which has overridden both the scientific and moral imperatives to implement proven interventions that could inflect the global TB curve more rapidly.6–8 Although standardization of treatment contributed to improved clinical outcomes for some people with TB, the absence of a comprehensive approach for fighting TB in high-burden settings has led to predictable and alarming results.3,9,10

More than 10 million people still fall sick from TB every year, including 1 million children.3,11 More than 3 million patients with TB remain undetected and continue to transmit the disease in their families and communities. Appropriate treatment for drugresistant TB remains the exception rather than the rule, allowing further transmission of these mutant strains. Most known contacts receive no post-exposure therapy even though it is a standard intervention in most high-income settings. Finally, and most damning of all, nearly 2 million people still die each year from TB—a preventable and curable disease.3

Ending the TB epidemic requires the urgent deployment of a comprehensive package of effective, tried-and-tested interventions in settings with high burdens of TB. This comprehensive approach must happen in tandem with the development of effective point-of-care diagnostics, highly effective and shorter treatment regimens, and vaccines. In this chapter, we review a set of proven epidemic-control strategies for combating the disease. Their wider and more systematic application, evidence suggests, will result in quantitatively greater and more rapid progress in tackling the global TB epidemic.1,2,12–18 Separately, the effect of each strategy might be modest; in combination, however, global experience and mathematical modelling suggest that they will have a swift and dramatic effect on TB incidence and mortality.1,2

A growing coalition is calling for the urgent, widespread implementation of these tried-and-tested approaches to stopping the disease.4,19 This will mean applying evidence-based strategies to search for and diagnose everyone who is sick with TB, to treat them promptly and effectively with the best medicines that cause the least adverse events, and to prevent future TB cases by stopping TB transmission and treating TB infection. These strategies will need to be implemented all at once in an integrated fashion in order to have the maximum effect.2 This approach is aligned with the Stop TB Partnership’s Global Plan to End TB, the principles of the World Health Organization’s end TB strategy, and the targets that emerged from the 2018 United Nations High-Level Meeting on TB.20–22 Multiple local coalitions are working to operationalize this comprehensive approach in geographically defined zones. This network of coalitions is called the Zero TB Initiative.23,24

Where—and how rapidly—can TB rates actually drop toward elimination? Policy discussion about so-called TB elimination (defined as less than one TB case per million population per year) is often only in reference to countries where TB incidence is already below 10 per 100,000 population per year.25 Notably, only about 12% of the world’s population lives in those countries.26 In contrast, more than 45% of the world’s population lives in countries where TB case rates exceed 100 per 100,000 per year. Thus, one step in the required paradigm shift is the perspective that—regardless of the size of the current local TB burden—every community coalition can aspire to drive down TB rates toward

elimination. Indeed, as a first step toward closing this gap in global health equity, local coalitions can devise plans to reduce TB case rates to below 10 per 100,000 per year.

Similarly, a new perspective is needed about how rapidly case reductions can be achieved. As noted, at the global level, since 2000 the number of new TB cases has declined at just 1.5% per year.5 In many settings, high TB case rates are essentially stagnant, with almost no change year after year. However, there are several locations where annual reductions in TB case rates have exceeded 15%. What these settings had in common was the simultaneous use of multiple strategies targeted in geographically defined zones: we refer to this as a comprehensive approach to driving down TB rates.

In this chapter, we will review examples of rapid TB declines (Part I) and review the three strands of activities that must be deployed simultaneously as a comprehensive approach: SEARCH−TREAT–PREVENT (Part II). Local coalitions can use these experiences and framework to inform how to tailor their own efforts to drive down TB rates one community at a time.

PART I: THE CASES

We identified illustrative examples in the literature where annual declines per year exceeded 5%. These are summarized in Table 21.1 and described in the following section.

Greenland

Greenland is the world’s largest island and part of the Kingdom of Denmark. In the early 1950s, a survey estimated that 2% of the population had TB—an incidence rate of approximately 2,000/100,000 population.42 In 1955, the population of the island was approximately 22,000. By then, Greenland had begun programs to reduce its TB burden, including “better” case-finding, “effective” hospitalizations and chemotherapy, and BCG vaccination for newborns and young children.

In 1955, a dedicated TB ship began annual visits to all villages on the island, offering free examinations for all, which included chest radiography, sputum examinations, TST, and BCG vaccination. Each year, the ship visited 90% of the population, with nearly 100% coverage achieved after two years. In 1956, the program added an interventional study through which about half of all villages received isoniazid preventive therapy, excluding individuals already on treatment for active TB and those under the age of 15. This meant that isoniazid preventive therapy was used to treat nearly 20% of the entire population of Greenland (half of the adults in the country who did not have active TB).

The comprehensive approach was ongoing, and 5 years after the start of the intervention TB incidence had declined from 2,000/100,000 to 1,051/100,000: a decline of nearly half. Six years after the isoniazid intervention began, the TB rate had declined by 66%—a decline of 17% per year.

State of Alaska

In 1959, Alaska became a US state.29,30,32,33,35,46 Prior to that, it was a US territory, having been purchased from Russia in 1867. In 1952, with a population of 190,000, the case rate for TB in Alaska was 379/100,000. BCG vaccination had been initiated in 1949 and was ongoing until 1956, when it was discontinued. In 1953, a United States Public Health Service commission was convened to provide recommendations on how to reduce rates of TB in Alaska. These recommendations included intensified case finding and outpatient treatment.

In 1955, an ambulatory chemotherapy program was introduced whereby patients received treatment for TB in their homes, rather than through lengthy hospital stays. In 1957, a randomizedcontrolled trial of isoniazid preventive therapy was initiated in the Bethel area; this trial randomized households to receive isoniazid or placebo in an effort to better understand the utility of community-wide preventive therapy for reducing TB in areas with a high disease burden. The only individuals who did not receive preventive therapy were those already on treatment for active TB, those with medical history suggesting epilepsy, and infants under 2 months of age. In the time that isoniazid was administered, the intervention group experienced a 68% reduction in rates of TB compared to the households that received placebo. Based on this success, isoniazid preventive therapy was expanded to the whole community in this area in 1963.

Five years after the interventions began, there had been a nearly 70% decline in TB case rates—from 299.1/100,000 to 98.2/100,000; an annual decline of 20%. By the early 1990s, Alaska’s rate of TB was comparable to that of the rest of the United States: around 10 cases or less per 100,000 population.

Western Palm Beach County

Palm Beach County is in the southeastern US state of Florida.36,37 The western portion of the county historically had higher rates of TB than the eastern portion: the average annual rate of TB cases in 1994–1997 was 81/100,000 in the western region, compared to 9.1 cases/100,000 population in the eastern region. In 1993, a team of investigators from the Palm Beach County Health Department, the Florida Department of Health, the CDC, Emory University, and Dartmouth Medical School gathered in order to develop a survey to assess the prevalence of both active and latent TB in western Palm Beach County.

A non-governmental organization, diverse and representative of the community, was formed in order to increase participation in the survey (which earlier assessments had indicated would be too low to gather meaningful measurements). This group initiated a community-based participatory intervention to reduce fears around stigma, confidentiality, and community reputation. They disseminated health messages about signs and symptoms of TB, availability of free treatment, rationale for the survey, and the importance of participation through a press conference; television and radio appearances; booths at community events; visits to local churches and clubs; and outreach to high-risk populations. The survey itself was conducted in a random selection of households in the region. Participants received TST and those with a positive result were referred to clinicians who performed chest radiography; participants then received treatment for active or latent TB as needed.

Concurrently, the county health department continued passive case-finding, and the intervention staff built a partnership with the health department and assisted in administering LTBI treatment to recently infected high-risk contacts of infectious TB patients. This approach resulted in a steep decline in TB rates in this region, which was faster than that observed in the eastern portion of the county. In 2002–2005, the average annual TB case rate was 25/100,000; an almost 70% reduction (a decline of nearly 20% per year) compared to 1994–1997; by 2006–2009, the rate was 19/100,000—a more than 75% reduction from the years prior to the intervention. Over this period, the average annual case rate in the eastern portion of the county decreased from 9.1/100,000 in 1994–1997 to 7.2/100,000 in 2006–2009—a roughly 20% decline.

New York City

In 1988, the number of TB cases in New York City had more than doubled compared to 10 years earlier; the number of TB patients tripled from 1978 to 1992.50 New York City’s population at that time was 7.3 million. From 1988 to 1994, funding for the New York City Department of Health increased 10-fold; the interventions deployed with these increased resources allowed for a more than 50% decline in TB case rates, from the 1992 peak of 51.3/100,000 to 23.3/100,000 in 1997.

Interventions introduced in this period included outreach workers traveling to patients’ homes to support treatment; improvement of infection control to reduce nosocomial infection; downsizing of large shelters and provision of non-congre- gate housing for people living with HIV; improvement of TB care among incarcerated persons; and introduction of a four-drug

regimen for treatment of TB disease. Laboratory testing methods were improved, drug susceptibility testing increased, a higher index of suspicion was used in diagnosis, and preventive therapy was expanded in high-risk groups.

With increased resources and improvements in case-find- ing, case notification rates continued to climb in 1988–1992. Subsequent to the peak case rate in 1992, TB rates declined by 15% per year over 5 years; by 2016, the rates had declined by more than 85% since the 1992 peak.

Two neighborhoods in Smith County, Texas

Texas is a large state in the United States.39 In 1996, a team of researchers from the University of Texas, the Texas Department of Health, and the Smith County Health Office sought to assess whether targeting interventions to neighborhoods with high burdens of TB could help to reduce future cases of the disease in those geographic areas. The Texas Department of State Health Services shared with the researchers the addresses of all cases of TB that were reported in Smith County from 1985 to 1995, along with the addresses of all individuals with positive TST results from 1993 to 1995.

With the addresses provided by the government, the team used a geographic information system to map cases of TB and instances of positive TST within Smith County, Texas. The mapping showed two neighborhoods with an unusually high TB burden, an average case rate of 39.6/100,000 in a population of 3,153 enumerated resi- dents—five times the average in the rest of the county. The coalition launched a community-wide screening intervention in these two neighborhoods, including: communication materials shared in churches and schools; public service announcements in local periodicals and TV/radio; door-to-door visits made by field workers to explain the project and offer free TSTs; free chest radiography and evaluation in mobile clinics for those participants with positive TSTs; treatment for those with active TB; and latent TB infection treatment for participants who had a positive TST result but who did not have active TB.

In the 10 years subsequent to the initial mapping, the team again mapped the cases of TB in Smith County. They found that, from 1996 to 2006, there had been no TB cases in the two neighborhoods targeted by the interventions; there was only one case in 2007. Rates of TB in the rest of the county and state had also declined, but much more slowly. In the two target neighborhoods, there was an annual decline in TB cases of 31%; in the county, the rate of TB declined at a rate of 5% per year, and in the state of Texas it declined at an annual rate of 4%.

State of Tennessee

Tennessee is a state in the United States that had a population of 5.7 million in the year 2000.52,53 At that time, Tennessee’s TB case notification rate (6.7/100,000 in 2000) had been above the national annual rate for two decades. With state funding, the Tennessee Department of Health initiated a statewide TB screening pro- gram—at the time, the only program of its kind—integrated with other public health services.

The program began in 2002 and, by the end of 2006, had screened almost 170,000 individuals who presented at county health departments for other public health services, and at some community sites (such as jails, shelters, and other high-risk settings). It sought to distinguish high-risk individuals who could benefit from TST from low-risk individuals among whom usage of TST could be limited, and to prevent development of active TB by expanding treatment of latent TB infection.

In 2006, Tennessee’s incidence of TB had approached and then dropped below the national rate. In 2010, Tennessee had three cases of TB/100,000 population, compared to the US rate of 3.6/100,000—an annual decline of 8% per year. (The state’s TB case notification rate fell below the national rate for the first time in more than 20 years.) From 2000 to 2011, Tennessee experienced a 64% reduction in TB case notification, compared to the national reduction of 41%.

PART II: THE APPROACH

The preceding examples, among others, show the simultaneous use of multiple strategies in one location. We summarize them as a set of Search, Treat, and Prevent components of a comprehensive approach to more rapidly drive down TB rates in specific geographic areas.

Search: Search actively, test properly

A person who is infected with TB bacteria can become sick with active TB disease. This can happen as quickly as a few weeks or months after infection, or as long as decades later. People with TB infection who become sick can transmit the infection to their families, communities, and places of work. Therefore, a crucial step in stopping the transmission of TB—and a fundamental tenet of tuberculosis epidemic control—is to actively search and treat people who are sick with TB or who have TB infection.

Of the more than 10 million people who became sick with TB in 2016, only 6.3 million were recorded and reported by national governments.54 This has been consistent over the last decade— yearly, almost 4 million people sick with TB and MDR-TB are “missed” by health systems. These people may be sick with TB and are never diagnosed or are treated in the private sector and were not recorded by national or international registers. Those who are not diagnosed or treated continue to transmit TB infection in their families, communities, and places of work. The large proportion of missed people with TB is a major cause of the slow progress in stopping the global TB epidemic.

DELAYS IN DIAGNOSIS CONTRIBUTE TO THE SPREAD OF TB

In most of the world, people with TB are diagnosed with the disease only after they seek care for their symptoms at a health care facility. A person can have TB for a long period without noticeable symptoms or with symptoms that are not severe enough for them to seek care. By the time people are sick enough to seek care, they may have been infectious for a long time.

Diagnosing people only after they seek care directly contributes to the spread of TB. A study of TB patients and their contacts in the United States found that patients with undiagnosed TB were more likely to pass on the TB infection to their contacts; the longer the delay in diagnosis, the more likely they were to have transmitted the infection. More than half of patients in the study had a delay of at least 90 days between having their first symptom and starting TB treatment, and 40% of the contacts of those patients had been infected with TB.55

TARGETED ACTIVE CASE-FINDING FINDS MORE TB CASES EARLIER

Targeted active case-finding involves actively seeking out and screening people who are at higher risk of becoming sick with TB.56 The strategy reduces transmission rates because it finds more people with TB and diagnoses them earlier, so that those who are infectious can be treated before they transmit TB to more people. Currently, targeted active case-finding activities for TB focus primarily on just a few of the key populations and groups with high exposure: contacts of people who have TB, including children; people living with HIV; and people who seek care at health facilities in areas where TB is prevalent.

Targeted active case-finding is effective in finding new TB cases among key populations and groups with high risk, and works better than mass screening of the entire population. Across many studies in lowand middle-income countries that examined the rates at which people sick with TB transmitted the infection to their contacts, an average of more than 3% of contacts had active TB disease and more than 50% of contacts had TB infection.57 The risk was highest during the first year of exposure, for children under 5 years of age, and for people living with HIV.58 A review of studies that used targeted active case-finding to screen people living with HIV for TB symptoms found that, on average, the strategy identified one additional case of TB for every 100 people who were screened.59 Many studies carried out in a range of settings have examined the impact of screening people who visit general healthcare facilities for TB, which finds new TB cases in an average of 5%−10% of the people screened.60,61,62,63 To optimize effectiveness, active case-finding efforts should be informed by local epidemiologic data.1,64

Table 21.2 summarizes the estimates of the percentage of new TB cases that will be found among people screened using different active case-finding activities.

Table 21.2  Expected yield of various active case-finding activities

ACTIVE CASE-FINDING REQUIRES PROPER TESTING AND DIAGNOSTIC TOOLS

Active case-finding activities are only as effective as the tests and diagnostic tools that are used. Countries with the highest TB burdens still rely heavily—and spend resources—on an older diagnostic test called sputum smear microscopy, in which a patient’s sputum sample is examined under a microscope for the presence of TB mycobacteria.

Compared with newer and more sensitive diagnostic methods, sputum smear microscopy is very unreliable: it has an overall failure rate of around 50%, meaning that half of people tested are “smear negative” despite having TB; in children, it fails to detect TB approximately 90% of the time.65 In people living with HIV, it fails to detect TB more than 70% of the time.66 Sputum smear microscopy cannot detect TB that develops outside of the lungs (extrapulmonary TB), nor can it determine if the person has drugresistant TB.67

Although they are generally less infectious than smear-positive patients, smear-negative patients can also transmit the disease to others. A study in the United States of more than 1,500 TB patients found that at least 17% had contracted TB from a smear-negative patient and around 27% had contracted it via a chain of transmission that began with a smear-negative patient.68

Relying only on smear microscopy for diagnosis causes many people who are sick with TB to remain undiagnosed and untreated while they continue to be infectious. More sensitive diagnostic tests are available that can detect a higher proportion of TB cases. These include combinations of the following diagnostic tools: radiography (chest X-ray); mycobacteriological culture; molecular diagnostic tests (such as the Xpert MTB/RIF test); and clinical algorithms.69 Bacteriological culture of a patient’s sputum sample is a very accurate diagnostic method (some types can also test for drug resistance) but the results can take 2–6 weeks, while new types of molecular diagnostic tests take only hours or days to identify people with drug-resistant TB.

Clinical algorithms for diagnosing TB can help to identify and promptly treat patients with forms of TB disease that are not confirmed by microbiological tests. Chest X-ray is a key tool in clinical algorithms because it is much more sensitive than sputum smear microscopy in detecting TB in the lungs. X-ray can also detect the most common forms of extrapulmonary TB. Children have trouble producing the sputum needed for TB diagnostic tests, including tests for drug resistance, so they should be treated for TB based upon clinical diagnosis.70 Clinical algorithms are an essential tool in diagnosing TB in children and people living with HIV, most of whom have smear-negative pulmonary TB or extrapulmonary TB that is not easily detectable using currently available diagnostic tools.71

ACTIVE CASE-FINDING REDUCES TB TRANSMISSION IN COMMUNITIES

Using targeted active case-finding reduces the rates at which TB disease and TB infection are transmitted in communities. A study in Brazil examined the effect of screening household contacts of people with TB. After 5 years, the communities where active casefinding was carried out had 10% fewer reported TB cases, which

Table 21.3  Projecting impact of increased TB case finding73

If 25% more TB cases are diagnosed and treated, then after 10 years:

•40%–44% fewer people will die from TB-related causes (mortality)

•22%–27% fewer people will be get TB each year (incidence)

•30%–33% fewer people will be sick with TB (prevalence)

was 15% lower than the number of cases reported in communities where household contacts were not screened.13 Studies in Zambia and South Africa reported similar results after 4 years: communities where household contacts of TB patients were screened had 18% lower rates of TB among adults and 55% lower rates of TB infection among children compared with communities where active case-finding was not used.72

ACTIVE CASE-FINDING CAN REDUCE THE BURDEN OF TB

The benefits of active case-finding accumulate over time, because finding and treating people with infectious TB prevents them from transmitting the disease to others. Projecting forward, mathematical models based on data from the current TB epidemics in China, India, and South Africa predict that targeted active case-finding can have a substantial impact on TB mortality, incidence, and prevalence (Table 21.3).73

This goal of a 25% increase in the number of detected cases is feasible with active case-finding activities. One study analyzed 19-year-long active case-finding activities, which were associated with a 35% increase in reported TB cases.74 Active case-finding activities are also highly cost-effective interventions because they help stop transmission. Active case-finding activities need to be linked directly to the delivery of prompt, effective treatment.

Treat: Treat effectively, support through treatment

Until they are treated effectively, people sick with TB disease remain infectious. Stopping the global TB epidemic will require treating people with the correct medications as quickly as possible after diagnosis.

For people with TB disease that is not drug resistant, treatment generally involves taking four different first-line drugs for a period of 6 months. That regimen will not cure drug-resistant TB disease, which requires treatment with a combination of five or more effective second-line drugs for as long as two years. The treatments for both types of TB disease are lengthy and the medicines used can cause side effects, so a key component of TB care delivery is to support each patient in completing the entire treatment regimen.

EFFECTIVE TB TREATMENT RAPIDLY REDUCES INFECTIOUSNESS

Diagnosis must be followed by prompt effective treatment, because people who are diagnosed with TB but are not treated immediately are more likely to transmit TB to others. Long delays between diagnosis and treatment further increase the risk of transmission. A study in China found that people who were treated 30 days or

more after diagnosis had a significantly higher chance of transmitting TB and, after 90 days without treatment, were 2.3 times as likely to transmit it.75

Evidence gathered over the past 60 years has shown that effective TB treatment very quickly reduces the chance that a patient will infect others, even while the patient is still culture-positive or smear-positive. A pivotal study in India during the 1950s found that TB patients being treated effectively in their homes were no more likely to transmit TB to their family members than TB patients who were being treated in sanatoria and isolated from their families.76

Studies that expose guinea pigs to patients with TB have shown that effective treatment makes a TB patient non-infectious very rapidly, often within 24 hours. In an early study, TB patients who had started treatment were 98% less likely to transmit TB to the guinea pigs than patients who had not yet started treatment; more recent studies have reported that patients receiving no or inadequate treatment for drug-resistant TB were the source of virtually all transmission to guinea pigs. Patients being treated for drugresistant TB were not infectious, even those who had started treatment within the past 2 weeks.77

WIDESPREAD TESTING FOR DRUG RESISTANCE CAN ENSURE EFFECTIVE TREATMENT

Some people develop drug-resistant TB (DR-TB) because they became sick with drug-susceptible TB in the past, but did not receive a complete and effective treatment regimen. However, people who are sick with DR-TB can also pass the DR-TB infection to other people, and are doing so at increasing rates. In fact, globally, most patients sick with DR-TB including multidrug-resistant TB (MDR-TB) have never previously been diagnosed with TB disease.

For example, in 2013, within the WHO European region, 14% of patients who had never been previously treated for TB had MDR-TB.67 Although the proportion of MDR-TB among patients who have previously been treated for TB is higher—in the WHO European region it is almost 50%—there are fewer actual patients in the retreatment group.

Some TB programs do not test a patient with TB for drug resistance until a standard first-line drug regimen (taking 6 months) has been unsuccessful. Once a sample is collected for conventional testing of drug resistance, the results can take further weeks or months. Thus, patients may have infectious, untreated, drugresistant disease for many months before being started on effective treatment. Treatment with inappropriate first-line drugs can cause patients with drug-resistant TB to develop more resistance to additional types of TB drugs (known as amplification of resistance); these patients also tend to have worse treatment outcomes and are more likely to relapse with TB after undergoing months of treatment.79

As with drug-susceptible TB, patients with drug-resistant TB quickly stop spreading the infection once they are treated with the correct regimen.77 Widespread testing for drug-resistant TB using new rapid molecular testing can shorten the delay in treating patients with the correct regimen, substantially reducing the time they are infectious. Such programs have been implemented in countries with high rates of drug-resistant TB and have proven to be feasible.

For example, a TB hospital in Russia tested all patients with symptoms suggestive of TB for drug resistance using Xpert within 2 days of admission. Within 10 months, more than 150 patients with MDR-TB were identified and started appropriate treatment within 5 days of diagnosis.80 The microscopic observation drug susceptibility (MODS) assay is a rapid test that can diagnose TB and test for drug resistance. In certain districts of Peru, the MODS assay was used to screen every patient who started treatment for TB. The result was a significant decrease in the time it took to diagnose patients with drug-susceptible TB (from 118 days to 33 days) and patients with MDR-TB (from 158 to 52 days).81

Standardized risk criteria can be used to guide decisions about treatment for drug-resistant TB in cases where tests for drug resistance are unavailable or the test results are pending. For example, if a child is clinically diagnosed with TB and lives in the same household as an adult with drug-resistant TB, then the child would be treated for drug-resistant TB. In the households of people with drug-resistant TB (source cases), when another person in a household also became sick with TB (secondary cases), the secondary case had the same pattern of drug resistance as the source case more than 50% of the time.82

STRENGTHENING HEALTH SYSTEMS CAN REDUCE TREATMENT DELAYS

Reducing the delay between diagnosis and treatment is critical for stopping transmission and ensuring that patients have the best chance for a good treatment outcome. Delays in initiating treatment for TB have been widely reported. For example, a study in South Africa reported that only 20% of patients with drug-resis- tant TB had started treatment within the 2 weeks after their diagnosis. MDR-TB patients faced an average delay of 17 days between diagnosis and treatment, despite having rapid nucleic acid test (Xpert MTB/RIF) results available within hours.83 Gaps in the health delivery systems can exacerbate treatment delay at multiple points in the process, but protocols can be put in place to initiate effective treatment promptly. Such practices include collecting accurate contact information for patients at the first diagnostic visit and optimizing the processes of receiving, accessing, and communicating results to patients.

PATIENTS NEED TO BE SUPPORTED THROUGHOUT TREATMENT

Patients can face numerous obstacles that result in treatment delays and uncompleted treatments. Not only must they be able to access treatment after diagnosis, but they must be willing and able to start and maintain the lengthy treatment regimen. Patients may choose to decline or stop treatment for various reasons: they may not feel very sick from the disease; treatment may interfere with their ability to work; or the nearest health facility may entail travelling long distances. Having TB remains stigmatized in many communities, causing some patients to become isolated or depressed. Additionally, TB is driven by poverty and is itself a driver of poverty, so specific support strategies are required to make treatment feasible for people suffering from the disease (Table 21.4).

Integrated care can reduce the burden of time and effort that TB treatment can impose upon patients, making them more likely to complete treatment. Depending on the specific setting, TB care

Table 21.4  Examples of strategies for supporting patients through TB treatment16,17,86

•Following up actively with people who do not start treatment

•Providing incentives and enablers for patients to start treatment

•Monitoring patients during treatment

•Providing transportation assistance and/or food assistance as needed

•Providing social support through treatment supporters and patient support networks

•Providing cash transfers to patients and/or their families

might be integrated into other public healthcare services such as HIV care, diabetes care, or maternal−child health programs.84 Partnerships with community advocates and other public sectors can bolster TB detection and treatment efforts, as can partnering with private hospitals and providers in areas where many patients seek care in the private sector.85 Approaches that address economic and social barriers to treatment adherence and completion are also important for a comprehensive TB program to be successful.86

Prevent: Prevent exposure, treat exposure

An estimated one-quarter of the global population is infected with TB (1.7 billion people), but most of those people will not become sick with active TB disease.87 People who are infected with TB but who are not sick make up a reservoir of potential future cases of TB, and it has been estimated that roughly 10% of them will eventually become sick with TB disease, 5% within the first 2 years after infection. A recent re-analysis of the published literature concludes that the vast majority of TB disease will occur within two years of TB infection.88 Even if health systems were able to find and instantly treat every new case of TB, or if there were an effective new vaccine for preventing TB, the epidemic would still not be stopped. People who are already infected will continue to become future TB cases and continue to spread the disease. Shrinking that reservoir of people who are infected with TB is the only way to stop the epidemic.89 This will require protecting people from exposure to TB mycobacteria and treating people who have been exposed to TB with preventive therapy.

PROTECTING PEOPLE FROM EXPOSURE PREVENTS FUTURE TB CASES

TB is an airborne disease that can be spread anywhere by any untreated patient with pulmonary TB, but transmission of TB is more likely in crowded, poorly ventilated settings and inside homes or healthcare facilities where people are sick with TB. In healthcare facilities, patients and staff can be protected from exposure by implementing simple practices such as isolating and providing paper masks for people with symptoms suggestive of TB90 and improving ventilation by opening windows and doors.91 Another strategy is screening people who live or work in settings with a higher exposure risk—such as mines, prisons, and factories—so that they can be treated and protect others from infection.

PREVENTIVE THERAPY FOR HIGH-RISK GROUPS REDUCES NEW TB CASES

People who are infected with TB bacteria have a 10% risk of becoming sick with TB disease at some point in their lives. Testing a person for TB infection can be done using the tuberculin skin test (TST) or the interferon gamma-release assay (IGRA) blood test. If a person tests positive for TB infection, then treatment with appropriate preventive therapy can significantly reduce the person’s chance of developing active TB disease. Treatment with isoniazid given daily for at least 6 months is the most common regimen for preventive therapy, but there are also other therapies that are shorter, easier to deliver, and shown to be as effective (e.g., isoniazid and rifapentine given once weekly for 3 months).78 Decades of clinical studies have shown that preventive therapy can keep people with TB infection from becoming sick with TB. In adults with TB infection who do not have HIV and have otherwise healthy immune systems, isoniazid preventive therapy can reduce the risk of developing active disease by 60%, and one person will be saved from TB if 35 infected people take isoniazid for 6 months.51

Although the average person infected with TB has a 10% lifetime risk of becoming sick with the disease at some point in their lives, some groups of people have an even higher risk of becoming sick with TB if they are infected with the TB bacteria, including: children, people living with HIV, and people who have other types of chronic illnesses.49 However, preventive therapy can significantly reduce the chance that people in these high-risk groups will become sick with TB if they are infected.

Among children with TB infection under the age of 16 years, preventive treatment with isoniazid reduces the risk of becoming sick with TB by more than 60%.78 Adults living with HIV who are also infected with TB have a 30% chance of developing active disease if they do not receive preventive therapy; treatment with 3–12 months of isoniazid therapy reduces that risk by between 32% and 62%.48 People infected with both HIV and TB who are being treated for HIV with antiretroviral therapy have a 60% lower chance of developing active TB, so combining TB preventive therapy with antiretroviral therapy has an even more powerful effect.47

SHORTER PREVENTIVE THERAPY REGIMENS CAN REDUCE THE TREATMENT BURDEN

The length of treatment and the potential side effects can make it difficult for patients to complete preventive therapy regimens, and health systems can have difficulty administering and monitoring patients’ treatments. However, preventive therapy regimens are available that are shorter but highly effective, and can ease the burden on both patients and health systems. These regimens include: 3–4 months of treatment with rifampin once daily; 3–4 months of treatment with rifampin plus isoniazid once daily; or 3 months of treatment with rifapentine plus isoniazid once weekly.89

PREVENTIVE THERAPY CAN ALSO REDUCE NEW CASES OF DRUG-RESISTANT TB

Clinical studies are still underway, and observational evidence suggests that appropriate preventive therapy can also protect

persons exposed to drug-resistant TB from developing active TB disease.45 A systematic review of 21 observational studies of MDR-TB preventive therapy found it to be 90% effective in preventing MDR-TB in close contacts and it was also cost-effective.44

PREVENTIVE THERAPY CAN HAVE A POPULATIONLEVEL IMPACT

In the 1950s, a groundbreaking study in the United States investigated using isoniazid preventive therapy to treat household contacts of people with TB. In households where contacts were treated, the number of new TB cases was 60% lower than in households where contacts were not treated; this reduced risk of developing TB was sustained for 20 years.43 More recent studies in Brazil looked at the effect of active case-finding combined with preventive therapy for household contacts of TB patients. After 5 years, the number of new TB cases was 10% lower in those communities, compared with a 5% increase of new TB cases in communities where household contacts were not screened.13 Another study screened patients enrolled in HIV clinics in Brazil and treated those who had TB infection with preventive therapy, which reduced the number of new TB cases among the clinics’ patient populations by between 25% and 30%.27

CONCLUSIONS

Local coalitions seeking to drive down TB rates can design a comprehensive strategy that integrates these three strands of activities—SEARCH, TREAT, and PREVENT—and that is tailored to the local epidemic. These efforts require collaboration among many stakeholders committed to driving down TB rates in specific locations: the public sector at the municipal, regional, and national levels; the private sector; academia; and civil society groups. The Zero TB Initiative is a learning community that promotes shared learning and disseminates lessons from these coalitions.23

REFERENCES

1.Lönnroth K, Jaramillo E, Williams BG, Dye C, and Raviglione M. Drivers of tuberculosis epidemics: The role of risk factors and social determinants. Social Sci Med. 2009; 68:2240–6.

2.Dye C, Glaziou P, Floyd K, and Raviglione M. Prospects for tuberculosis elimination. Annu Rev Public Health. 2013; 34:271–86.

3.World Health Organization. Global Tuberculosis Report 2014. Geneva: WHO, 2014.

4.Zero TB Declaration. Treatment Action Group. Available at http://www.treatmentactiongroup.org/tb/advocacy/zerodeclaration (accessed July 19, 2015).

5.WHO. Global Tuberculosis Report 2015. Geneva, Switzerland: World Health Organization, 2015.

6.Keshavjee S, Farmer PE. Tuberculosis, drug resistance and the history of modern medicine. N Engl J Med. 2012;367(10):931–6.

7.McMillan CW. Discovering Tuberculosis: A Global History 1900 to the Present. New Haven and London: Yale University Press, 2015.

8.Walsh JA, and Warren KS. Selective primary health care: An interim strategy for disease control in developing countries. N Engl J Med. 1979;301:967–74.

9.Obermeyer Z, Abbott-Klafter J, and Murray CJL. Has the DOTS strategy improved case finding or treatment success? An empirical assessment. PLOS ONE. 2008;3(3):e1721. doi:10.1371/journal.pone.0001721

10.De Cock KM, and Chaisson RE. Will DOTS do it? A reappraisal of tuberculosis control in countries with high rates of HIV infection. Int J Tuberc Lung Dis. 1999;3(6):457–65.

11.Jenkins HE, Tolman AW, Yuen CM, Parr JB, Keshavjee S, Pérez-Vélez CM, Pagano M, Becerra MC, and Cohen T. Incidence of multidrug-resistant tuberculosis disease in children: Systematic review and global estimates. Lancet. 2014;383(9928):1572–9.

12.Frieden TR, Fujiwara PI, Washko RM, and Hamburg MA. Tuberculosis in New York City—Turning the tide. N Engl J Med. 1995;333(4):229–33.

13.Cavalcante SC, Durovni B, Barnes GL, Souza FB, Silva RF, Barroso PF, Mohan CI, Miller A, Golub JE, and Chaisson RE. Community-randomized trial of enhanced DOTS for tuberculosis control in Rio de Janeiro, Brazil. Int J Tuberc Lung Dis. 2010;14(2):203–9.

14.Bamrah S et al. Treatment for LTBI in contacts of MDR-TB patients, Federated States of Micronesia, 2009–2012. Int J Tuberc Lung Dis. 2014;18(8):912–8.

15.Graham NM et al. Effect of isoniazid chemoprophylaxis on HIV-related mycobacterial disease. Arch Intern Med. 1996;156:889–94.

16.Keshavjee S et al. Treating multi-drug resistant tuberculosis in Tomsk, Russia: Developing programs that address the linkage between poverty and disease. Ann New York Acad Sci. 2008;1136:1–11.

17.Rocha C et al. The innovative socio-economic interventions against tuberculosis (ISIAT) project: An operational assessment. Int J Tuberc Lung Dis. 2011;15(5):S50–57.

18.Comstock GW. Isoniazid prophylaxis in an underdeveloped area. Am Rev Respir Dis. 1962;86:810–22.

19.Keshavjee S, Dowdy D, and Swaminathan S. Stopping the body count: A comprehensive approach to move towards zero tuberculosis deaths. Lancet. 2015;386:e46–7.

20.Available at: http://www.stoptb.org/global/plan/plan2/ (accessed May 31, 2019).

21.Available at: https://www.who.int/tb/strategy/end-tb/en/ (accessed May 21, 2019).

22.Resolution A/RES/73/3 adopted by the United Nations General Assembly on 10 October 2018 following approval by the high-level meeting of the General Assembly on the fight against tuberculosis on 26 September 2018. Available at: https://www.who.int/tb/unhlmonTBDeclaration.pdf

23.Available at: https://www.zerotbinitiative.org/ (accessed May 31, 2019).

24.Proceedings: The emerging role of municipalities in the fight against tuberculosis. Dubai, UAE: Harvard Medical School Center for Global Health Delivery—Dubai, 2015. Available

at: https://www.zerotbinitiative.org/http://ghd-dubai. hms.harvard.edu/files/ghd_dubai/files/municipalities_ v1n3april2015.pdf (accessed September 4, 2018).

25.WHO. Towards Tuberculosis Elimination: An Action Framework for Low-Incidence Countries.Geneva,Switzerland: World Health Organization, 2014.

26.World Health Organization. Global tuberculosis database. Available at: http://www.who.int/tb/data/en/ (accessed April 24, 2018).

27.Durovni B et al. Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: A stepped wedge, cluster-randomised trial.

Lancet Infect Dis. 2013;13:852–58.

28.Horwitz O, Payne PG, and Wilbek E. Epidemiological basis of tuberculosis eradication: 4. The isoniazid trial in Greenland. Bull WHO. 1966;35(4):509–26.

29.Chandler B. Alaska’s ongoing journey with tuberculosis: A brief history of tuberculosis in Alaska and considerations for future control. State of Alaska Epidemiol Bull: Recomm Rep. 2017;19(1).

30.Fraser RI. Tuberculosis in Alaska in 1965. Alaska Med. 1965;7:12–5.

31.Comstock GW, Baum C, and Snider DE, Jr. Isoniazid prophylaxis among Alaskan Eskimos: A final report of the Bethel isoniazid studies. Am Rev Respir Dis. 1979:119(5):827–30.

32.Comstock GW, Ferebee SH, and Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis. 1967;95(6):935–43.

33.Comstock GW, Philip RN. Decline of the tuberculosis epidemic in Alaska. Public Health Rep. 1961;76:19–24.

34.Hanson ML, Comstock GW, and Haley CE. Community isoniazid prophylaxis program in an underdeveloped area of Alaska. Public Health Rep. 1967;82(12):1045–56.

35.Porter ME, and Comstock GW. Ambulatory chemotherapy in Alaska. Public Health Rep. 1962;77:1021–32.

36.O’Donnell MR et al. Sustained reduction in tuberculosis incidence following a community-based participatory intervention. Public Health Action. 2012;2(1):23–6. doi:10.5588/ pha.11.0023.

37.O’Donnell MR et al. Racial disparities in primary and reactivation tuberculosis in a rural community in the southeastern United States. Int J Tuberc Lung Dis. 2010;14(6):733–40.

38.Frieden TR et al. Tuberculosis in New York City—Turning the tide. NEJM. 1995;333(4):229–33.

39.Cegielski JP et al. Eliminating tuberculosis one neighborhood at a time. Am J Public Health. 2014;104(Suppl 2):S225–33.

40.Cain KP et al. Moving toward tuberculosis elimination: Implementation of a statewide targeted tuberculin testing in Tennessee. Am J Respir Crit Care Med. 2012;186(3):273–9.

41.American Lung Association. Trends in Tuberculosis Morbidity and Mortality. American Lung Association Research and Health Education, Epidemiology and Statistics Unit. 2013. Available at: http://www.lung.org/assets/docu- ments/research/tb-trend-report.pdf

42.Horwitz O, Payne PG, and Wilbek E. Epidemiological basis of tuberculosis eradication: The isoniazid trial in Greenland. Bull WHO. 1966;35(4):509–26.