Download Drug-resistant TB in the United States

1
Epidemiology
& Background
3rd edition contributors: JENNIFER M. FLOOD, MD, MPH & LISA PASCOPELLA, PhD, MPH
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Drug-resistant TB across the globe. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Drug-resistant TB in the United States. . . . . . . . . . . . . . . . . . . . . . . . . 3
Sources of drug-resistant TB in the United States . . . . . . . . . . . . . . . 7
How is drug resistance generated?. . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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EPIDEMIOLOGY &
BACKGROUND
Efforts to control TB throughout the world
have been challenged in recent decades
by the emergence of drug-resistant TB.
Drug-resistant tuberculosis (TB) is a deadly communicable disease that poses a serious
global health threat. It impacts not only individual patients and their families, but also
imposes tremendous burdens on overextended public health systems that may lack the
resources needed to contain it.
DEFINITIONS
• Multidrug-resistant (MDR)
refers to TB caused by
Mycobacterium tuberculosis (M. tuberculosis) that is resistant to at
least isoniazid (INH) and rifampin (RIF).
• Pre-extensively drug-resistant (Pre-XDR)
refers to
MDR-TB that is also resistant to either a fluoroquinolone or a
second-line injectable anti-TB drug (kanamycin, capreomycin, or
amikacin), but not both.
• Extensively drug-resistant (XDR)
refers to MDR-TB that
is also resistant to both a fluoroquinolone and a second-line
injectable anti-TB drug.
Drug-resistant TB across the globe
In 2014, an estimated 480,000 people developed MDR-TB and 190,000 people died
from MDR-TB. By 2015, 105 countries had reported at least one case of XDR-TB.
An estimated 21% of MDR-TB cases worldwide have additional resistance to a
fluoroquinolone, and 9.7% have XDR-TB. According to the World Health Organization
(WHO), more than half of the global burden of MDR-TB is currently in three countries:
India, China, and the Russian Federation.
Worldwide and in most countries with a high burden of MDR-TB, WHO estimates that in
2014 only 41% of those with MDR-TB were actually diagnosed by laboratory
testing.
Fortunately, there are new and vigorous efforts for control of TB and for early diagnosis
and treatment of drug-susceptible and drug-resistant TB worldwide. Large-scale implementation of rapid molecular tests for early detection of both the presence of TB and, at
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WHO reported improvements in detection and treatment of MDR-TB in 2014: 111,000
people with MDR-TB were started on second-line treatment, equivalent to 90% of the
123,000 newly-detected cases that were reported and eligible for treatment globally.
However, treatment coverage gaps for detected cases were much larger in some
countries, notably the high-burden countries of China (49%), Myanmar (44%), and Nigeria (53%).
Finally, improvements in early identification and enrollment into treatment must also be
followed by quality of care measures that ensure treatment success. Only three high-burden countries reported a treatment success rate for MDR-TB of 75% or higher. On average, only 50% of MDR-TB patients in the 2012 cohort of detected cases were
treated successfully. Many countries lack the resources needed to provide sufficient
quality of care. These disparities must be addressed to prevent further transmission of
disease and more extensive resistance.
In many high-burden countries, a standardized MDR-TB regimen is used due to the lack
of routine access to second-line drug-susceptibility testing (DST). The success or failure
of treatment of these cases overseas can impact the presentation of drug resistance in
the United States (U.S.) through immigration. It is important for U.S. clinicians to understand the diversity of global practices.
A milestone for improved MDR-TB care occurred in 2012 when bedaquiline (BDQ)
fumarate (Sirturo, Janssen) became the first TB drug in a novel class to be approved in
40 years. In October 2013, the U.S. Centers for Disease Control and Prevention (CDC)
issued provisional guidance for its use in the treatment of MDR-TB. A second new drug,
delamanid (Deltyba, Otsuka), also gained provisional approval for use in the European
Union in 2014, and additional drugs are in the development pipeline.
Drug-resistant TB in the United States
In the United States in 2010-2013:
• 413 TB patients had MDR-TB based on initial DST. Of these, 49 patients had preXDR-TB, and 12 patients had XDR-TB. In other words, 15% of U.S. MDR-TB patients
had pre-XDR or XDR.
• Thirty-eight states plus the District of Columbia reported at least 1 MDR-TB case;
19 states reported at least 1 pre-XDR-TB case; and 8 states reported at least 1
XDR-TB case. See Figure 1.
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EPIDEMIOLOGY &
BACKGROUND
a minimum, rifamycin resistance has occurred in many high-burden countries. The
Patients’ Charter for Tuberculosis Care, developed by the World Care Council, promotes
a “patient-centered” approach to tuberculosis care. The updated International Standards
for Tuberculosis Care (ISTC) presents a set of widely accepted, evidence-based standards describing a level of care that all practitioners, public and private, should seek to
achieve in managing patients with, or suspected of having, TB.
EPIDEMIOLOGY &
BACKGROUND
FIGURE 1.
Drug-resistant TB in United States, 2010-2013
41,195 TB cases reported
31,519 (77%) TB cases with positive cultures
30,978 (98%) TB cases with positive cultures and DST done
2,794 (9%) INH-resistant TB cases
413 (1.3%) MDR TB cases
49 (12%)
pre-XDR TB cases
12 (3%)
XDR TB cases
Although the number of drug-resistant cases of TB in the United States declined as the
number of total reported TB cases decreased, there has been little change in the percentage (1.0 –1.6%) of TB patients with MDR-TB during 2000-2013. On the other hand,
the percentage of patients with INH resistance has increased from 7.9% in 2000 to 9.2%
in 2013. The increase in INH-resistant TB is troubling because it is one mutation away
from becoming MDR-TB.
In recent years, the percentage of patients with pyrazinamide (PZA)-resistant TB has also
increased (from 2.0% to 3.3% during 1999-2009). TB patients with PZA resistance include
those with TB infections caused by M. bovis (a member of the M. tuberculosis complex
that is intrinsically resistant to PZA) and M. tuberculosis. M. bovis accounted for an average of 1.7% of culture proven cases from 2008-2013.
In the United States, drug resistance in foreign-born persons with TB is much more common than in U.S.-born persons with TB, corresponding to the higher rates of drug resistance in the countries of origin.
• In 2013, 90% of MDR-TB cases in the United States were among foreign-born
persons.
• Among foreign-born patients who arrived in the United States within 2 years of
TB diagnosis (recent arrivers), 3.2% had MDR-TB, compared to 1.4% of those
diagnosed with TB more than 2 years after they arrived (remote arrivers).
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EPIDEMIOLOGY &
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Figure 2 shows that the percentage of U.S.-born TB patients with INH resistance increased
from 4.5% to 5.8% from 2000 to 2013. Among foreign-born TB patients over the same
time period, the percentage of INH-resistant TB remained the same, at about 11% in both
recent and remote arrivers.
FIGURE 2.
U.S.-born INH resistant TB cases and percentages, 2000-2013
6.1%
5.8%
6.3%
5.6%
5.2%
4.5%
300
294
4.6%
4.3%
4.5%
4.6%
232
232
230
4.5%
4.2%
4.4%
185
182
5.8%
273
250
210
200
203
201
181
182
150
150
139
100
50
0
|
|
|
|
|
|
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|
|
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20002001 20022003200420052006 200720082009201020112012 2013
Cases per year
Percent of all U.S.-born cases INH resistant
The small percentage of U.S.-born TB patients with
MDR-TB slightly declined from 2000 (0.6%, N=42) to
2013 (0.4%, N=9), while the percentage of foreign-born
recent (3%, N=33) and remote (1.4%, N=47) arrivers with
MDR-TB remained stable over the same time period.
INH-resistant TB among
U.S.-born patients slightly
increased from 2000-2013.
Rates of INH-resistant and
MDR-TB among all groups
have otherwise remained
stable during this period.
Overall, drug-resistant TB is also more common among
TB patients who were born in countries with an estimated
high prevalence of drug resistance. Discordance between
WHO and U.S. estimates of MDR-TB by country-of-origin
was documented in a recent study that demonstrated that
the U.S. National TB Surveillance system (NTSS) better
predicted the prevalence of drug resistance in foreignborn U.S. residents with TB than the WHO/International Union Against Tuberculosis and
Lung Diseases (IUATLD) Global Project on Anti-Tuberculosis Drug Resistance Surveillance (Global DRS). Of the 413 foreign-born patients diagnosed with MDR-TB in the
United States from 2010 to 2013, 75% were born in only 15 countries. Table 1 shows the
drug resistance pattern for the top 15 countries of origin for cases of drug-resistant TB in
the United States.
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TABLE 1.
Drug resistance among foreign-born TB patients in the United States,
2010-2013 (Top 15 countries)
Country of origin
Total TB
cases*
MDR
Any resistance**
INH resistance
No.
%
No.
%
No.
%
India
2,122
40
1.9
258
12.2
166
7.8
Philippines
3,068
39
1.3
484
15.8
386
12.6
Mexico
5,542
37
0.7
652
11.8
324
5.8
Vietnam
2,002
32
1.6
365
18.2
293
14.6
China
1,478
23
1.6
162
11.0
133
9.0
Peru
373
14
3.8
51
13.7
38
10.2
Laos
284
12
4.2
49
17.3
36
12.7
93
12
12.9
21
22.6
17
18.3
Haiti
753
11
1.5
58
7.7
53
7.0
Republic of Korea
461
11
2.4
56
12.1
54
11.7
Burma / Myanmar
426
9
2.1
60
14.1
47
11.0
Dominican Republic
296
8
2.7
31
10.5
27
9.1
Ecuador
307
8
2.6
31
10.1
26
8.5
Guatemala
777
8
1.0
61
7.9
49
6.3
Ethiopia
635
7
1.1
60
9.4
58
9.1
Ukraine
*Total cases with positive cultures and initial susceptibilities performed
**TB isolates with any first-line drug resistance (INH, RIF, ethambutol [EMB], PZA)
Source: Robert H. Pratt, National Tuberculosis Surveillance System, Division of Tuberculosis Elimination, Centers for Disease Control and Prevention
(email communication, November 14, 2014).
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MDR-TB: A staggering cost for a small percentage of TB cases
A 2014 study by Marks, et al., of MDR-TB patients in the United States in 2005-2007 determined that
the direct costs to treat drug-resistant TB averaged $134,000 per MDR-TB patient and $430,000 per
XDR-TB patient. In contrast, the estimated cost per non-MDR-TB patient was $17,000.
Sources of drug-resistant TB in the
United States
There are 4 primary sources that explain the epidemiology of drug-resistant TB in the
United States:
• Resistance acquired during treatment in the United States
• Recent transmission of drug-resistant M. tuberculosis
• Reactivation of latent drug-resistant TB infection
• Entry of patients into the United States with active drug-resistant M. tuberculosis disease
A cross-sectional study of 92 MDR-TB cases reported in the United States 2007-2009
determined that:
• 5% of patients had a documented previous episode of TB in the United States
and likely relapsed with acquired drug-resistant disease.
• 22% of MDR-TB cases were the result of recent transmission.
• 41% had reactivation disease (one-third of those with reactivation disease had a
previous episode of TB in another country, indicating possible acquired resistance
outside of the United States).
• Another 22% occurred in patients originating from another country who
entered the United States with active TB disease.
• 10% could not be classified because there were insufficient data.
MDR-TB transmission has been documented across the world, with a 2010 report of half
of MDR-TB cases occurring within individuals with newly-identified TB (rather than previously-treated TB), in 30 countries.
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Drug resistance is also more common in TB patients who reported having had
previous TB. In the United States in 2013, 4.2% of all patients who reported previous TB
had MDR-TB, whereas only 1.2% of patients who did not report previous TB had MDR-TB.
These differences in percentages with MDR-TB were evident among both U.S.-born
patients (2.2% with previous TB vs. 0.3% without previous TB) and foreign-born patients
(5.1% with previous TB vs. 1.7% foreign-born patients without previous TB).
EPIDEMIOLOGY &
BACKGROUND
How is drug resistance generated?
Drug resistance is generated at the molecular level when genes responsible for the specific form of drug resistance (e.g., rpoB for rifampin) of M. tuberculosis develop a spontaneous mutation. The prevalence of resistant mutants associated with each first-line
drug used to treat TB has been estimated, and resistance to new drugs (e.g., bedaquiline)
has already been identified. A typical pulmonary cavity will contain an
estimated 107 to 109 organisms, therefore making it likely that some organisms in
these cases may exhibit a spontaneous mutation for resistance. See Table 2.
TABLE 2.
Select anti-tuberculosis drugs and prevalence of resistant
mutants
Year
introduced
Prevalence of resistant
mutants within a wild-type
population of M. tuberculosis
bacteria
Streptomycin
1945
3.8 x 10 -6
Isoniazid
1952
3.5 x 10 -6
Pyrazinamide
1952
1.0 x 10 -5
Ethambutol
1962
3.1 x 10 -5
Rifampin
1967
1.2 x 10 -8
Bedaquiline
2013
Drug
?
Within wild-type populations, resistance to more than one TB drug is even rarer as resistance to the various drugs is not linked genetically. Inherent resistance to more than one
TB drug is the product of the prevalence of resistance to the individual drugs.
• INH and RIF: 3.5 x 10 -6 x 1.2 x 10 -8 equals 4.2 x 10 -14
Mutations conferring drug resistance to M. tuberculosis become important for the TB
patient when amplified by health care system-related factors and/or patient behaviors.
Contributors to the development of acquired resistance during treatment for TB include:
inadequate clinical management, poor adherence, drug malabsorption, and unstable
drug supply. Enhancers of transmission of MDR-TB include factors that extend the
infectious period; e.g., delayed diagnosis and/or delayed treatment initiation with an
appropriate regimen, and delayed bacteriological conversion of sputum. Inadequate
infection control can also contribute to transmission of MDR-TB.
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• The patient may not take all the drugs prescribed, due to any of the following
factors:
• Lack of resources
•Intolerance/toxicity
•Misunderstanding
• Interrupted drug supply
• Disbelief in the diagnosis
• Disbelief in the efficacy or necessity of the treatment
• Chaotic lifestyle; substance abuse
• Cultural issues
•Pregnancy
• Neuropsychiatric disease
• There may be a dispensing or administration error regarding the correct dose.
• The patient may not be prescribed the appropriate dose.
• The patient may not absorb the full dose of medication and/or have disease in areas
where the penetration of one or more of the drugs may be impaired.
• The provider may not prescribe an adequate TB regimen.
• The patient’s organism may already be resistant to one of the TB drugs prescribed,
leaving an unrecognized suboptimal TB regimen.
• The patient may have been incorrectly diagnosed as having latent TB infection
(LTBI), rather than active TB disease, and treated with monotherapy.
• The TB patient may be taking therapy for another disease. That therapy may coincidentally contain a single drug active against TB (rifabutin in an HIV patient for Mycobacterium avium complex [MAC] prophylaxis; a fluoroquinolone for communityacquired pneumonia).
• The patient may take TB medicines without a prescription (sometimes available
over-the-counter outside the United States, or if taking medications belonging to
someone else).
• The TB medicines may interact with other drugs being taken by the patient.
If the patient starts an effective TB regimen and then stops
taking all the TB drugs at the same time, the population of
bacteria usually remains susceptible.
This is one of the major advantages of directly observed therapy (DOT): either the
patient takes all the drugs or none of the drugs. This is also the benefit of combination
formulations such as INH/RIF or INH/RIF/PZA in a single product. The patient either
takes all drugs or none—reducing risk of development of resistance.
Clinically significant drug resistance usually emerges after 1 to 3 months of administration of an inadequate drug regimen.
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In a patient with active TB disease, factors that create or amplify drug resistance include:
EPIDEMIOLOGY &
BACKGROUND
Summary
• Globally in 2014, an estimated 480,000 people developed MDR-TB and
190,000 people died from MDR-TB. By 2015, 105 countries had
reported at least one case of XDR-TB. More than half of the global
burden of MDR-TB is currently in three countries: India, China, and the
Russian Federation.
• Despite recent improvements in early identification and enrollment into
treatment, high-burden countries often lack the resources needed to
ensure quality of care for treatment success.
• Ninety percent of MDR-TB cases in the United States occur among the
foreign-born.
• Fifteen percent of MDR-TB patients in the United States had pre-XDR
or XDR-TB.
• Risk factors for INH-resistant and MDR-TB in the United States include
country-of-origin, recent arrival (within 2 years) in the United States,
previous TB, and exposure to an individual with INH-resistant or
MDR-TB during the infectious period.
• The percentage of TB patients with MDR-TB is not increasing in the
United States, but the percentage of U.S.-born TB patients with INH
resistance, and PZA resistance overall, is increasing in the United
States.
• The increase in INH-resistant TB is troubling because it is one mutation
away from becoming MDR-TB.
• It is essential to implement strategies to assure DOT and completion of
an adequate regimen in order to reduce development or amplification of
drug resistance.
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• Andries K, Villellas C, Coeck N, et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline.
PLoS ONE. 2014;10;9(7):e102135.
• Caminero JA. Multidrug-resistant tuberculosis: epidemiology, risk factors and case finding. Int J Tuberc
Lung Dis. 2010;14:382-390.
• Canetti G. Present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis. 1965; 92: 687-703.
• Centers for Disease Control and Prevention. Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR.
2013;62(No. RR-9).
• Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 2013. Atlanta,
GA: U.S. Department of Health and Human Services, CDC, October 2014.
• Kurbatova EV, Cavanaugh JS, Dalton T, Click ES, Cegielski JP. Epidemiology of pyrazinamide-resistant
tuberculosis in the United States, 1999-2009. Clin Infect Dis. 2013;57(8):1081-1093.
• Marks SM, Flood J, Seaworth B, et al. Treatment practices, outcomes, and costs of multidrug-resistant
and extensively drug-resistant tuberculosis, United States, 2005–2007. Emerg Infect Dis. 2014;20(5):
812-820.
• Moonan PK, Teeter LD, Salcedo K, et al. Transmission of multidrug-resistant tuberculosis in the USA: a
cross-sectional study. Lancet Infect Dis. 2013;13(9):777-784.
• Royce S, Falzon D, van Weezenbeek C, et al. Multidrug resistance in new tuberculosis patients: burden
and implications. Int J Tuberc Lung Dis. 2013;17(4):511-513
• Taylor AB, Kurbatova EV, Cegielski JP. Prevalence of anti-tuberculosis drug resistance in foreign-born
tuberculosis cases in the U.S. and in their countries of origin. PLoS ONE. 2012;7(11) e49355.
• World Care Council. Patients’ Charter for Tuberculosis Care. 2006. Available at: http://www.currytbcenter.ucsf.edu/international-research#patients-charter. Accessed November 1, 2015.
• World Health Organization. Drug-Resistant TB Surveillance & Response. Supplement: Global Tuberculosis Report 2014. Available at: http://www.who.int/tb/publications/global_report/gtbr14_supplement_
web_v3.pdf. Accessed December 30, 2015.
• World Health Organization. Global Tuberculosis Report, 2015. Available at: www.who.int/tb/publications/
global_report/en/. Accessed December 30, 2015.
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References
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