Medical
Journal Examines Treatment of Extensively Drug-resistant Tuberculosis as First
Survey of Cases Is Reported in California By
Liz Highleyman Tuberculosis
(TB) is among the leading causes of death among people with HIV/AIDS
worldwide. Multidrug-resistant TB (MDR-TB) is widespread among this population,
and extensively drug resistant TB (XDR-TB) is a growing public health threat,
especially in resource-limited countries. As of June 2008, a total of 49 countries
had reported at least 1 case of XDR-TB. Researchers
first raised the alert about XDR-TB
among people with HIV/AIDS at the 2006 International AIDS Conference in Toronto.
But XDR-TB is not limited to people with HIV nor to those in poor countries. Extensively
Drug-Resistant Tuberculosis (XDR TB)
Diminishing Options for Treatment |  | | XDR
TB occurs when a Mycobacterium tuberculosis strain is resistant to
isoniazid and rifampin, two of the most powerful first-line drugs, as well as
key drugs of the second line regimen—any fluoroquinolone and at least one of the
three injectable drugs shown above. XDR TB strains may also be resistant to additional
drugs, greatly complicating therapy. |
|
XDR-TB
in California In
the August 15, 2008 issue of Clinical Infectious Diseases, public health
investigators reported results of the first survey of XDR-TB in California.
California
reports almost 3000 cases of TB annually, the authors noted as background, and
since 2002 the state has led the nation in the number of MDR-TB cases.
The
authors analyzed case reports submitted to the state TB registry from 1993 through
2006. Local health departments and the state TB laboratory were queried to ensure
complete drug susceptibility reporting.
XDR-TB
was defined as TB with resistance to at least isoniazid, rifampin, a fluoroquinolone,
and 1 of 3 injectable second-line drugs (amikacin, kanamycin, or capreomycin).
Pre-XDR TB was defined as TB with resistance to isoniazid and rifampin and either
a fluoroquinolone or a second-line injectable agent, but not both.
Results
•
Among 424 MDR-TB
cases with complete drug susceptibility data, 18 (4%) were XDR and 77 (18%) were
pre-XDR.
•
The proportion
of pre-XDR cases increased over time, from 7% in 1993 to 32% in 2005 (P = 0.02).
•
83% of XDR-TB
cases involved foreign-born individuals, and 43% were diagnosed within 6 months
after arriving in the U.S.
•
Mexico was
the most common country of origin for patients with XDR-TB.
•
5 cases (29%)
of XDR-TB were acquired during treatment in California.
•
All patients
with XDR-TB had pulmonary disease (as opposed to outside the lungs).
•
Most had prolonged
infectious periods, with a median time of 195 days for conversion of sputum culture
results.
•
Among 17 patients
with known outcomes, 7 (41%) completed treatment, 5 (29%) moved, and 5 (29%) died;
1 patient was still on therapy when the report was submitted.
Based
on these findings, the investigators wrote, "XDR-TB and pre-XDR TB cases
comprise a substantial fraction of MDR-TB cases in California, indicating the
need for interventions that improve surveillance, directly observed therapy, and
rapid drug susceptibility testing and reporting."
"Globally,
XDR-TB has resulted from a combination of poor TB control practices, poor adherence
to medications, inappropriate use of second-line drugs, lack of laboratory capacity
to culture TB or assess drug susceptibility, and high HIV prevalence," author
Ritu Banerjee of the University of California at San Francisco said in a media
release issued by the Infectious Diseases Society of America. "In order to
prevent an escalation in XDR-TB we need to ensure adherence to the cornerstones
of TB management, which include directly observed therapy, isolation of infectious
cases, and contact investigations."
Department of Pediatrics,
Division of Infectious Disease, University of California, San Francisco, CA; Tuberculosis
Control Branch and Microbial Diseases Laboratory, California Department of Public
Health, Richmond, CA; Tuberculosis Control Program, Los Angeles County Department
of Health, Los Angeles, CA.
XDR-TB
Treatment Given
its resistance to all first-line and several second-line drugs, treatment of XDR-TB
remains a challenge. However, it can be cured with appropriate and aggressive
management. The
August 7, 2008 issue of the New England Journal of Medicine included 2
reports and an editorial concerning therapy for extensively resistant TB.
Study
1
In
the first report, Carole Mitnick of Harvard Medical School and colleagues describe
the management of XDR-TB and treatment outcomes among patients referred for individualized
outpatient therapy in Lima, Peru.
Between 1999 and 2002, a total of 810
patients were referred for free therapy, including drug treatment, surgery, management
of side effects, and nutritional and psychosocial support. Most patients had long-standing
tuberculosis, probably reflecting progressive accumulation of drug-resistance
mutations during prior inadequate treatment, rather than acquisition of already
highly resistant bacteria.
The investigators tested TB isolates from 651
patients for drug resistance and devised a customized regimen that included at
least 5 drugs to which the isolates were still sensitive, including cycloserine
(an injectable drug) and a fluoroquinolone.
Results
•
Of the 651
patients tested, 48 (7.4%) had XDR-TB; the remaining 603 had MDR-TB.
•
Patients with
XDR-TB had undergone more treatment than the other patients (mean 4.2 vs 3.2 regimens;
P < 0.001) and had isolates that were resistant to more drugs (8.4 vs 5.3;
P < 0.001).
•
None of the
patients with XDR-TB were HIV positive.
•
Most patients
were treated for more than 2 years.
•
29 of the XDR-TB
patients (60.4%) completed treatment or were cured, compared with 400 MDR-TB patients
(66.3%) -- not a statistically significant difference (P = 0.36).
•
11 XDR-TB patients
(23%) died of the disease.
"Extensively
drug-resistant tuberculosis can be cured in HIV negative patients through outpatient
treatment, even in those who have received multiple prior courses of therapy for
tuberculosis," the investigators concluded.
"It is noteworthy
that the outcomes in our study were better than most outcomes reported from hospitals
in Europe, the United States, and Korea, where cure was achieved in fewer than
half of patients with extensively drug-resistant tuberculosis," they added
in their discussion.
"It's essential that the world know that XDR-TB
is not a death sentence," Mitnick said in a media release issued by Harvard.
"It's important for people to understand that this ambulatory form of treatment
exists, is successful, and can be widely implemented in resource-poor settings."
However,
XDR-TB therapy for HIV positive people can be considerably more complex and difficult,
and the disease is associated with a higher mortality rate, due to immune suppression
and concern about interactions between anti-TB drugs and antiretroviral agents.
Study
2
In
a correspondence in the same issue, Edward Chan of the National Jewish Medical
and Research Center in Denver and colleagues described treatment of patients with
XDR-TB at their specialty medical center for respiratory diseases.
The
investigators previously reported on 205 consecutive patients with MDR-TB referred
to their center between 1984 and 1998. The overall long-term success rate was
75% and the rate of death due to TB was 12%. In the present study, they retrospectively
analyzed these 205 cases of to determine what percentage met the definition of
XDR-TB and what were the outcomes in this subgroup.
Results
•
In the overall
cohort of 205 MDR-TB patients, 174 underwent sufficient drug susceptibility testing
to definitively determine whether they met the definition of XDR-TB.
•
Of these 174
patients, 10 (6%) were classified as having XDR-TB.
•
The median
rate of drug resistance was 68% among patients with XDR-TB compared with 45% for
those with MDR-TB (P < 0.001).
•
Patients with
MDR-TB were about 20 times more likely to be successfully treated than those with
XDR-TB (odds ratio 23.4 for initial outcome, P < 0.001; 21.1 for long-term
outcome, P < 0.001).
•
Patients with
XDR-TB were about 8 times more likely to die from TB or surgery compared with
the MDR-TB group (hazard ratio 7.9; P < 0.001).
•
The hazard
ratio for death from any cause was 2.5 (P = 0.07).
"Despite
aggressive treatment at our referral center, extensively drug-resistant tuberculosis,
as compared with multidrug-resistant tuberculosis, was associated with a significantly
poorer initial treatment response and long-term outcome and a significantly lower
survival rate," the investigators concluded. "These data underscore
the critical importance of optimal management of cases of multidrug-resistant
tuberculosis, lest they develop into extensively drug-resistant tuberculosis." Editorial In
an accompanying editorial commentary, Mario Raviglione of the World Health Organization's
Stop TB Partnership called the results of the Peruvian study "encouraging"
and "a true change in the current perception of [XDR-TB] as a virtual death
sentence."
However, he noted that other studies -- including the
Denver analysis -- have not produced comparable success rates, leading him to
suggest that perhaps the TB strains in Peru were not quite as drug resistant as
usual for XDR-TB.
Raviglione emphasized the rigorous and closely supervised
treatment protocol in the Peruvian study, stating that strict supervision is essential
in managing tuberculosis, particularly when second-line drugs are used, since
"creating additional drug resistance will exacerbate an already catastrophic
situation in the individual patient while creating the basis for dissemination
in the community."
However, he added, supervision did not consist
of merely watching people take their drugs, but rather "had all the elements
of support for successful long-term treatment": it was community-based for
most patients, thus avoiding the stress of prolonged hospitalization, included
psychological support for people taking potentially toxic drugs, and included
nutritional support and financial incentives.
"In 2008, scaling up
is indeed the major challenge faced by most complex health interventions worldwide,
especially when health systems and services are not optimal," he concluded.
"Ultimately, the effectiveness of a complex intervention depends on coordinated
work among all forces. The Peru experience is a clear example that, in this spirit,
even the most difficult objectives can be reached. The challenge is to make this
approach a sustainable reality worldwide."
|
8/26/08 References R
Banerjee, J Allen, J Westenhouse, and others. Extensively Drug-Resistant Tuberculosis
in California, 1993-2006. Clinical Infectious Diseases 47(4): 450-457.
August 15, 2008. (Abstract)
CD Mitnick,
SS Shin, KJ Seung, and others. Comprehensive treatment of extensively drug-resistant
tuberculosis. New England Journal of Medicine 359(6): 563-574. August 7,
2008. (Abstract)
ED Chan,
MJ Strand, and MD Iseman. Treatment outcomes in extensively resistant tuberculosis
[Correspondence]. New England Journal of Medicine 359(6): 657-659. August
7, 2008. (Abstract)
MC Raviglione.
Facing extensively drug-resistant tuberculosis -- a hope and a challenge [Editorial].
New England Journal of Medicine 359(6): 636-638. August 7, 2008. (Abstract)
Other sources
Infectious Diseases Society of America. Extensively
drug-resistant tuberculosis found in California. Press release. August
13, 2008.
Harvard Medical School. Comprehensive treatment of extensively
drug-resistant TB works, study finds. Press release. August 7, 2008.
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