Harris is going to love this: more evidence of *cures*.

Zee

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Multi-Drug Resistant TB Persists in California

WASHINGTON, D.C. - Despite significant advances in reducing the number
of cases of tuberculosis in California, the proportion of multi-drug
resistant cases has not decreased but remains steady, according to a
study in the June 8 issue of JAMA, a theme issue on tuberculosis.

Lead author Reuben M. Granich, M.D., M.P.H., of the Centers for Disease
Control and Prevention, Atlanta, presented the findings of the study at
a JAMA media briefing on tuberculosis at the National Press Club.

The number of tuberculosis (TB) notified cases has decreased by 33
percent in California, from 1994 to 2003, according to background
information in the article. TB nevertheless continues to have a
substantial public health impact, leading to 233 deaths in 2003.
California led the nation in 2003 in the number of cases. Additionally,
cases of TB due to strains of Mycobacterium tuberculosis that are at
least resistant to the mainstay first-line drugs isoniazid and rifampin
(i.e., multidrug-resistant [MDR] strains) continue to appear in
California despite high rates of treatment success. The emergence of
these life-threatening, airborne strains, which require prolonged
treatment for at least 18 months and exhibit higher rates of treatment
failure and poorer outcomes, threatens the efficacy of TB control
efforts.

Treatment of patients with drug resistance requires considerable
expertise and resources; health care cost estimates for individual MDR
TB patients in the United States range from $28,217 to $1,278,066. MDR
TB has also been associated with serious sizeable hospital and
community outbreaks in California and the greater United States.

Dr. Granich and colleagues analyzed drug susceptibility data in the
California TB surveillance system to describe the magnitude, trends,
geographic distribution, clinical characteristics, risk factors, and
outcomes of drug-resistant TB cases to better understand the impact of
resistance to multiple drugs on TB control in California and to plan
public health interventions. The analysis included 38,291 TB cases
reported from all 61 local health jurisdictions in California during
1994-2003. Multidrug-resistant TB was defined as resistance to at least
isoniazid and rifampin.

Of 38,291 reported TB cases, 28,712 (75 percent) were tested for
resistance to at least isoniazid and rifampin. The researchers found
that of these, 407 MDR TB cases (1.4 percent) were reported from 38 of
61 California health jurisdictions (62 percent); the proportion of
MDR-TB cases did not significantly change over the study period.

Cases of MDR TB were 7 times more likely to have reported previous
treatment for TB compared with non-MDR TB cases. Of MDR TB cases with
outcomes, 231 (67 percent) completed therapy, and those with MDR TB
were significantly less likely to complete therapy than those without
MDR TB.  Further analysis identified previous TB diagnosis, positive
results when examining sputum for the TB germ under a microscope,
Asian/Pacific Islander ethnicity, time in the United States less than 5
years at the time of diagnosis, and outcomes of "died" and "moved" as
factors associated with MDR TB.

"Our findings are of concern and suggest that the cases of MDR TB in
California may have appeared for any of 3 reasons: importation of MDR
strains from outside the state, endogenous development of MDR strains
due to inadequate case management or poor treatment within California,
or ongoing transmission," the authors write.

The researchers found that MDR TB was strongly associated with birth
outside the United States: 83 percent of MDR TB cases were foreign
born, from 30 different countries.

"The findings of our study have several clear implications for TB
control efforts. First, the fact that the majority of MDR TB cases were
foreign born highlights both the importance of international TB control
(prevention of MDR development and transmission abroad) as well as the
need to expand overseas screening programs to encompass additional
high-risk groups, coupled with measures to ensure timely detection and
treatment of MDR TB once it develops. Second, our results suggest that
adherence to recommended TB treatment guidelines must be improved to
ensure that poor case management does not contribute to further cases
of MDR within California.

"Third, the higher proportion of individuals moving or lost to
follow-up, as well as the longer time to culture conversion and
clinical characteristics favoring transmission, suggest that measures
to reduce transmission and improve outcomes are also necessary. Fourth,
additional resources (e.g., additional staff, regional centers of
excellence, and 'warm lines' that provide clinical consultations) are
needed because an increasingly large proportion of MDR cases appear to
be arising in rural or smaller health jurisdictions with limited
resources and expertise; the threat of MDR TB is exacerbated by a
shrinking pool of clinicians experienced in managing these complex
patients, who require intensive monitoring (e.g., drug levels,
second-line drug susceptibilities, and renal function) over an 18- to
24-month period," the authors write.

The researchers add that to help support the efforts of local programs
to manage patients with complex MDR- TB, the California Department of
Health Services TB Control Branch established an MDR- TB clinical
service that provides clinical support, collaborates with model
centers, and will participate in the efforts of the Centers for Disease
Control and Prevention to support several TB consultation medical
training centers. "Our study suggests that clinicians should consider
MDR TB in younger persons with TB who are Asian and/or Pacific
Islander, non-U.S.-born from countries with known MDR TB epidemics,
recent arrivals (less than 5 years) in the United States, and those
reporting prior TB treatment."

"Multidrug-resistant TB requires complex management decisions, and
additional resources will be required to successfully interrupt
transmission and cure patients through timely diagnosis, treatment with
adequate drug regimens and DOT, and through a patient-centered approach
to ensure adherence. Although MDR TB may be curable at a great
individual and societal cost, the implementation of both local and
global TB control strategies is needed to prevent the further
development and spread of MDR TB," the researchers conclude.

(JAMA. 2005;293:2732-2739. Available pre-embargo to the media at
www.jamamedia.org)

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Treatment Helps in Preventing TB Among Those at High Risk

WASHINGTON, D.C. - The drug isoniazid reduced the incidence of
tuberculosis among HIV-infected miners in South Africa, a population at
high risk of TB, according to a study in the June 8 issue of JAMA, a
theme issue on tuberculosis.

Lead author Alison D. Grant, M.B.B.S., Ph.D., of the London School of
Hygiene and Tropical Medicine, London, presented the findings of the
study at a JAMA media briefing on tuberculosis at the National Press
Club.

A major consequence of the human immunodeficiency virus (HIV) epidemic
in developing countries is the increasing incidence of tuberculosis
(TB), according to background information in the article. The
cornerstone of TB control programs is the World Health Organization
(WHO) strategy known as DOTS (directly observed therapy, short course),
which may be effective in controlling drug resistance but has not
prevented rising TB incidence in regions with high HIV prevalence.

The impact of HIV on TB is illustrated by data from gold mines in South
Africa, where overall TB incidence now exceeds 4,000 per 100,000
population per year (i.e., 4 percent). Tuberculosis incidence was
already high in this setting before the spread of HIV infection,
largely because of a high prevalence of silica dust exposure. Rising
HIV prevalence has resulted in increasing TB incidence, despite
well-implemented TB control programs. Additional interventions are
required to reverse the rise of TB in such settings.

In collaboration with the mining health service, the study team
established a clinic for HIV-infected employees in a gold mining
company in South Africa in 1999 to provide specialist care for
HIV-infected employees, including preventive therapy (isoniazid and
cotrimoxazole).  This study evaluates the effect of this intervention.
The authors analyzed 1,655 HIV-infected males (median age, 37 years)
attending the clinic between 1999 and 2001 (before antiretroviral
therapy was available). Median follow-up was 22.1 months.  Employees
were invited in random sequence to attend a workplace HIV clinic.
Isoniazid, 300 mg/d, was self-administered for 6 months among attendees
with no evidence of active tuberculosis.

A total of 1,016 of 1,655 men included in the analysis attended the
clinic at least once. Six hundred seventy-nine (97 percent) of 702 men
eligible to start primary isoniazid preventive therapy did so. The
researchers found that the tuberculosis incidence rate before vs. after
clinic enrollment was 11.9 vs. 9.0 per 100 person-years, respectively
(incidence rate ratio [IRR] after adjustment for calendar period, 0.68
[32 percent reduced incidence]). In further analysis adjusting for
calendar period, age, and silicosis grade, the tuberculosis IRR for
clinic enrollment was 0.62 (38 percent reduced incidence). In analysis
excluding individuals with a history of tuberculosis (and, hence,
ineligible for isoniazid preventive therapy), the adjusted IRR for
clinic enrollment was 0.54 (46 percent reduced incidence).

"Despite our intervention, the TB incidence rate in the postclinic
phase remained unacceptably high at 9 per 100 person-years," the
authors write.

"Additional interventions such as secondary preventive therapy and
antiretroviral therapy [which is now being rolled out among the
workforce] are required to reduce the very high residual morbidity
attributable to TB in this community. Further work is needed to
determine how best to use available interventions to minimize TB
morbidity in areas where both HIV and TB are highly prevalent," the
researchers conclude.

(JAMA. 2005;293:2719-2725. Available pre-embargo to the media at
www.jamamedia.org)

Editor's Note: This study was funded by Anglogold PTY Ltd. Dr. Grant is
supported by a U.K. Department of Health Public Health Career Scientist
award. Co-author Dr. Corbett is supported by a Wellcome Trust Career
Development Fellowship. Co-author Dr. Chaisson is supported by a
National Institutes of Health grant.

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Chest X-Rays Not Effective in Determining When TB Acquired

WASHINGTON, D.C. - There is little correlation between the appearance
of tuberculosis on chest x-rays and how recently the disease was
acquired, according to a study in the June 8 issue of JAMA, a theme
issue on tuberculosis.

Co-author Neil W. Schluger, M.D., of Columbia University, New York,
presented the findings of the study at a JAMA media briefing on
tuberculosis at the National Press Club.

Traditionally, active tuberculosis (TB) disease has been classified as
either primary or secondary, reflecting the time between initial
infection with Mycobacterium tuberculosis (MTB) and the onset of
clinical disease, according to background information in the article.
That interval can range over many years.  Primary and secondary TB are
also thought to have different characteristic radiographic (x-ray) and
clinical features, though these clinical observations have been based
on studies conducted before the availability of molecular
fingerprinting techniques for TB.  Molecular (DNA) fingerprinting, also
known as restriction fragment length polymorphism (RFLP) analysis is a
method for comparing strains of MTB from individual patients on a
genetic basis.  These techniques allow comparison of patients who have
recently acquired tuberculosis to those whose tuberculosis was acquired
long ago.

The researchers in this study used molecular fingerprinting and
conventional epidemiology to test whether recently transmitted cases
have radiographic features distinct from distantly acquired infection
and secondly, whether the atypical features of the radiograph in
HIV-associated TB are due to recent infection or are manifestations of
altered immunity in the reactivation of latent infection.  The study
included 546 patients treated at a New York City medical center between
1990 and 1999. Eligible patients had to have had at least 1 positive
respiratory culture for Mycobacterium tuberculosis and available
radiographic data.

The researchers found that in ". clinically well-defined patients with
TB that the most significant independent predictor of radiographic
appearance is HIV status," the authors write. "The altered radiographic
appearance of pulmonary tuberculosis in HIV is due to altered immunity
rather than recent acquisition of infection and progression to active
disease."

Although a clustered fingerprint (a DNA fingerprint from an MTB strain
from one patient which has an exact match with an MTB strain recovered
from at least one other patient), representing recently acquired
disease, was associated with typical radiograph, the association was
lost when adjusted for HIV status.

"In summary our findings argue that the terms primary and reactivation
TB are misleading when used to make inferences linking radiographic
findings to epidemiologic characteristics of patients. Radiographic
findings have implications regarding host immune status of patients,
but whether a patient's disease is due to recently transmitted or
remotely acquired infection cannot be determined from them," the
authors conclude.

(JAMA. 2005;293:2740-2745. Available pre-embargo to the media at
www.jamamedia.org)

Editor's Note: Supported in part by a grant from the National Heart,
Lung, and Blood Institute of the National Institutes of Health.

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Goals for TB Control Reachable for Most of World

WASHINGTON, D.C. - International goals for reducing the number of
tuberculosis cases and deaths to a certain number by the year 2015 can
be achieved, but African and Eastern European countries could pose the
greatest challenges, according to a study in the June 8 issue of JAMA,
a theme issue on tuberculosis.

Lead author Christopher Dye, D.Phil., from the World Health
Organization, Geneva, Switzerland, presented the findings of the study
at a JAMA media briefing on tuberculosis at the National Press Club.

In 1991, it was estimated that eight million people developed
tuberculosis (TB) each year and that several million people die from
the disease, according to background information in the article. In
response to this, the World Health Assembly of the World Health
Organization (WHO) set 2 targets for TB control: to detect 70 percent
of new cases and to successfully treat 85 percent of these cases.

Dye and colleagues conducted a study to determine if these goals will
be met in 2005, as well as the goal of halving TB prevalence and deaths
globally between 1990 and 2015. The researchers used data from DOTS
(initially an acronym referring to directly observed treatment and now
the term used for the WHO-recommended approach to TB control that
includes five essential elements) and non-DOTS programs reported
annually to the WHO by up to 200 countries, which includes the
information needed to assess TB incidence, prevalence and deaths
statistics. The elements of DOTS include political commitment; TB
detection by sputum smear; standardized drug treatment (including
directly observed therapy); a system to ensure regular drug supplies;
and a standard reporting system, including treatment outcomes
evaluation. Countries were grouped into nine different regions: African
countries with a high HIV infection rate (four percent or greater in
adults), African countries with a low HIV infection rate (less than
four percent), Central Europe, Eastern Europe, Eastern Mediterranean,
industrialized countries, Latin America, Southeast Asia, and Western
Pacific.

Many countries began using DOTS and other TB control programs in the
1990s. The researchers found that the number of new TB cases increased
globally in 2003 by about 1 percent, although new cases, total cases,
and death rates were approximately stable or decreased in seven of the
nine regions. The exceptions were regions of Africa with low (less than
4 percent in adults 15-49 years) and high rates (4 percent or greater)
of HIV infection. Detection of new smear-positive cases by DOTS
programs increased from 11 percent in 1995 to 45 percent in 2003 (with
the lowest case-detection rates in Eastern Europe and the highest rates
in the Western Pacific) and could reach 60 percent by 2005. More than
17 million patients were treated in DOTS programs between 1994 and
2003, with overall treatment success rates more than 80 percent since
1998. The overall treatment success rate was 82 percent in 2003, with
variation among regions. The highest rates were reported in the Western
Pacific region at 89 percent, with the lowest rates in African
countries with high and low HIV infection rates (71 percent and 74
percent, respectively), in industrialized countries (77 percent), and
in Eastern Europe (75 percent).

To halve the prevalence rate by 2015, TB control programs must reach
global targets for detection (70 percent) and treatment success (85
percent) and also reduce the incidence rate by at least 2 percent
annually. To halve the death rate, incidence must decrease more
steeply, by at least 5 percent to 6 percent annually, the researchers
write.

"Although the global incidence rate of TB was, in our assessment, still
increasing slowly in 2003 (about 1 percent per year), this increase
could be reversed by further reductions in transmission in high-burden
countries," the authors write.

They add that the difficulties of managing TB in Africa and Eastern
Europe are closely linked to HIV/AIDS and drug resistance, and specific
solutions will be needed for these problems in these regions.

The authors write that the vigorous implementation of an enhanced
strategy for TB control, bringing in new technology and a greater
diversity of clinicians and other health care workers, should give most
countries the momentum needed to reach the [United Nation's] Millennium
Development Goals by 2015. "The mission to control tuberculosis in
African and Eastern Europe will be more challenging, but until that
task has been accomplished, TB will remain a major concern for public
health worldwide."

(JAMA. 2005; 293: 2767 - 2775.  Available pre-embargo to the media at
www.jamamedia.org.)

Editor's Note: This work was funded by the World Health Organization.

# # #

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Risk Factors for Tuberculosis and Homelessness Often Overlap in U.S.

CHICAGO - Risk factors for tuberculosis in the United States overlap
with many of the risk factors associated with persistent homelessness,
including being male or having a history of incarceration or substance
abuse,  according to a report in the June 8 issue of JAMA, a theme
issue on tuberculosis.

"Homelessness is associated with an increased risk of exposure to
Mycobacterium tuberculosis, undetected and untreated infection, and
subsequent progression to TB disease," according to background
information in the article.  "In 1993, the Centers for Disease Control
and Prevention (CDC) standardized national monitoring of TB disease
among homeless persons by asking health departments to indicate whether
annually reported TB cases occurred in homeless persons," the authors
note.   "Thus, 1994 through 2003 represents the first full decade of
national TB surveillance that includes an assessment of homelessness."

Maryam B. Haddad, M.S.N., M.P.H., F.N.P., and colleagues from the CDC's
Division of Tuberculosis Elimination, analyzed data of all verified TB
cases reported into the National TB Surveillance System from 50 states
and the District of Columbia from 1994 through 2003 to compare risk
factors and disease characteristics between homeless and nonhomeless
persons with TB.

The authors note that because the U.S. Census Bureau does not have data
on the number of homeless people in the United States they were unable
to use the surveillance data to determine rates of TB disease among the
homeless and instead calculated the proportion of all reported TB cases
that occurred in homeless persons.

"Of 185,870 cases of TB disease reported between 1994 and 2003, 11,369
were among persons classified as homeless during the 12 months before
diagnosis," the authors report.  "The annual proportion of cases
associated with homelessness was stable (6.1 percent - 6.7 percent)."
The authors found a higher proportion of TB cases associated with
homelessness in western and some southern states.    "Most homeless
persons with TB were male (87 percent) and aged 30 to 59 years.  Black
individuals represented the highest proportion of TB cases among the
homeless and nonhomeless.  The proportion of homeless persons with TB
who were born outside the United States (18 percent) was lower than
that for nonhomeless persons with TB (44 percent).  At the time of TB
diagnosis, nine percent of homeless persons were incarcerated."  The
authors continue, "Compared with nonhomeless persons, homeless persons
with TB had a higher prevalence of substance use (54 percent alcohol
abuse, 29.5 percent noninjected drug use, and 14 percent injected drug
use), and 34 percent of those tested had coinfection with human
immunodeficiency virus."   Most of the TB cases in homeless persons
were managed by health departments (81 percent) and 86 percent of those
cases used directly observed therapy where healthcare professionals
watched the patients take their medications.

"The most urgent priority for controlling TB in the United States is
interrupting new transmission of M tuberculosis.  Opportunities for
transmission arise when homeless persons with infectious TB frequent
homeless shelters, emergency departments, and jails," the authors
write.   "Once diagnosed, however, homeless TB patients received good
case management, including laboratory diagnostic evaluation,
appropriate use of a 4-drug regimen, and excellent treatment outcomes
for persons given DOT [directly observed therapy] (recommended for all
TB patients).   Controlling this public health problem demands
considerable resources but is integral to responding to the Institute
of Medicine's call to eliminate TB in the United States," the authors
conclude.

(JAMA. 2005;293:2762-2766.  Available pre-embargo to the media at
www.jamamedia.org)

Editor's Note: Please see the JAMA study for funding information.

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JAMA Editorial: Tuberculosis - A Global Problem

CHICAGO - In an editorial for the June 8, 2005 JAMA theme issue on
tuberculosis, JAMA's Editor-in-Chief, Catherine D. DeAngelis, M.D.,
M.P.H., and Managing Deputy Editor Annette Flanagin, R.N., M.A., write,
"Some developed countries, such as the United States, have had
declining numbers of individuals infected with TB over the past decade,
but 23 countries account for 80 percent of all new TB cases, with more
than half concentrated in 5 countries (Bangladesh, China, India,
Indonesia, and Nigeria).  Most new cases in the United States, and
probably a substantial proportion of new cases in other developed
countries, occur among individuals born in other countries.  Clearly,
TB is a global health problem."

"The articles in this theme issue of JAMA devoted to TB address a
number of important concerns including screening; treatment for active
and latent infections; multidrug-resistant strains; and improving
screening, treatment, and quality of care for all vulnerable
populations.  These are serious problems that must be solved before TB
can be controlled."

"We hope that the insight provided by the various articles in this
issue of JAMA will stimulate more interest in better funding for
research on the prevention, screening, and treatment of TB and more
initiatives to use current knowledge to improve access to appropriate
and effective care and thereby successfully control TB.  Clearly, it
will take the will and resources of the entire world to eradicate this
global problem."

(JAMA. 2005; 293:2793-2794.  Available pre-embargo to the media at
www.jamamedia.org.)



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