Epidemiology of tuberculosis in a high HIV prevalence population provided with enhanced diagnosis of symptomatic disease.
ABSTRACT Directly observed treatment short course (DOTS), the global control strategy aimed at controlling tuberculosis (TB) transmission through prompt diagnosis of symptomatic smear-positive disease, has failed to prevent rising tuberculosis incidence rates in Africa brought about by the HIV epidemic. However, rising incidence does not necessarily imply failure to control tuberculosis transmission, which is primarily driven by prevalent infectious disease. We investigated the epidemiology of prevalent and incident TB in a high HIV prevalence population provided with enhanced primary health care.
Twenty-two businesses in Harare, Zimbabwe, were provided with free smear- and culture-based investigation of TB symptoms through occupational clinics. Anonymised HIV tests were requested from all employees. After 2 y of follow-up for incident TB, a culture-based survey for undiagnosed prevalent TB was conducted. A total of 6,440 of 7,478 eligible employees participated. HIV prevalence was 19%. For HIV-positive and -negative participants, the incidence of culture-positive tuberculosis was 25.3 and 1.3 per 1,000 person-years, respectively (adjusted incidence rate ratio = 18.8; 95% confidence interval [CI] = 10.3 to 34.5: population attributable fraction = 78%), and point prevalence after 2 y was 5.7 and 2.6 per 1,000 population (adjusted odds ratio = 1.7; 95% CI = 0.5 to 6.8: population attributable fraction = 14%). Most patients with prevalent culture-positive TB had subclinical disease when first detected.
Strategies based on prompt investigation of TB symptoms, such as DOTS, may be an effective way of controlling prevalent TB in high HIV prevalence populations. This may translate into effective control of TB transmission despite high TB incidence rates and a period of subclinical infectiousness in some patients.
Article: Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized controlled trial.[show abstract] [hide abstract]
ABSTRACT: To determine the efficacy of isoniazid 300 mg daily for 6 months in the prevention of tuberculosis in HIV-1-infected adults and to determine whether tuberculosis preventive therapy prolongs survival in HIV-1-infected adults. Randomized, double-blind, placebo-controlled trial in Nairobi, Kenya. Six hundred and eighty-four HIV-1-infected adults. Development of tuberculosis and death. Three hundred and forty-two subjects received isoniazid and 342 received placebo. The median CD4 lymphocyte counts at enrolment were 322 and 346 x 10(6)/l in the isoniazid and placebo groups, respectively. The overall median follow-up from enrolment was 1.83 years (range, 0-3.4 years). The incidence of tuberculosis in the isoniazid group was 4.29 per 100 person-years (PY) of observation [95% confidence interval (CI) 2.78-6.33] and 3.86 per 100 PY of observation (95% CI, 2.45-5.79) in the placebo group, giving an adjusted rate ratio for isoniazid versus placebo of 0.92 (95% CI, 0.49-1.71). The adjusted rate ratio for tuberculosis for isoniazid versus placebo for tuberculin skin test (TST)-positive subjects was 0.60 (95% CI, 0.23-1.60) and for the TST-negative subjects, 1.23 (95% CI, 0.55-2.76). The overall adjusted mortality rate ratio for isoniazid versus placebo was 1.18 (95% CI, 0.79-1.75). Stratifying by TST reactivity gave an adjusted mortality rate ratio in those who were TST-positive of 0.33 (95% CI, 0.09-1.23) and for TST-negative subjects, 1.39 (95% CI, 0.90-2.12). Overall there was no statistically significant protective effect of daily isoniazid for 6 months in the prevention of tuberculosis. In the TST-positive subjects, where reactivation is likely to be the more important pathogenetic mechanism, there was some protection and some reduction in mortality, although this was not statistically significant. The small number of individuals in this subgroup made the power to detect a statistically significant difference in this subgroup low. Other influences that may have diluted the efficacy of isoniazid include a high rate of transmission of new infection and rapid progression to disease or insufficient duration of isoniazid in subjects with relatively advanced immunosuppression. The rate of drug resistance observed in subjects who received isoniazid and subsequently developed tuberculosis was low.AIDS 07/1997; 11(7):875-82. · 6.24 Impact Factor
Article: Integration of tuberculosis screening at an HIV voluntary counselling and testing centre in Haiti.[show abstract] [hide abstract]
ABSTRACT: To describe the integration of tuberculosis screening into the activities of an HIV voluntary counselling and testing (VCT) centre in a country with endemic tuberculosis. An HIV VCT centre in Port au Prince, Haiti. All patients presenting for HIV VCT who reported cough received same-day evaluation for active tuberculosis. Of the 1327 adults presenting to the centre for the first time between January and April 1997, 263 (20%) reported cough and of these 241 (92%) were evaluated. Of the 241 patients evaluated for cough, 76 (32%) were diagnosed with pulmonary tuberculosis. Of the 76 patients diagnosed with pulmonary tuberculosis, 28 (37%) had a positive smear for acid-fast bacilli (AFB), 14 (18%) had a negative AFB smear but a positive sputum culture for Mycobacterium tuberculosis, and 34 (45%) had culture-negative tuberculosis. Also, 31 out of 241 (13%) VCT clients evaluated for cough were diagnosed with bacterial pneumonia. This report confirms that in areas with a high HIV and tuberculosis prevalence, a high proportion of VCT clients have active pulmonary tuberculosis. The integration of tuberculosis screening offers several benefits, including the diagnosis and treatment of large numbers of individuals with tuberculosis, a decreased risk of nosocomial tuberculosis transmission, and the opportunity to provide tuberculosis prophylaxis to HIV-positive patients in whom tuberculosis has been excluded. Future studies are needed to determine the cost-effectiveness of integrated tuberculosis and HIV VCT services, and whether integration should be recommended in all countries with high HIV and tuberculosis rates.AIDS 10/2001; 15(14):1875-9. · 6.24 Impact Factor
Article: Low access to a highly effective therapy: a challenge for international tuberculosis control.[show abstract] [hide abstract]
ABSTRACT: To determine the scale of the tuberculosis (TB) problem facing the international Stop TB Partnership by measuring the gap between present rates of case detection and treatment success, and the global targets (70% and 85%, respectively) to be reached by 2005 under the WHO DOTS strategy. We analysed case notifications submitted annually to WHO from up to 202 (of 210) countries and territories between 1980 and 2000, and the results of treatment for patients registered between 1994 and 1999. Many of the 148 national DOTS programmes in existence by the end of 2000 have shown that they can achieve high treatment success rates, close to or exceeding the target of 85%. However, we estimate that only 27% of all the new smear-positive cases that arose in 2000 were notified under DOTS, and only 19% were successfully treated. The increment in case-finding has been steady at about 133 000 additional smear-positive cases in each year since 1994. In the interval 1999- 2000, more than half of the extra cases notified under DOTS were in Ethiopia, India, Myanmar, the Philippines, and South Africa. With the current rate of progress in DOTS expansion, the target of 70% case detection will not be reached until 2013. To reach this target by 2005, DOTS programmes must find an additional 333 000 cases each year. The challenge now is to show that DOTS expansion in the major endemic countries can significantly accelerate case finding while maintaining high cure rates.Bulletin of the World Health Organisation 02/2002; 80(6):437-44. · 4.64 Impact Factor
Epidemiology of Tuberculosis in a High HIV
Prevalence Population Provided with Enhanced
Diagnosis of Symptomatic Disease
Elizabeth L. Corbett1,2*, Tsitsi Bandason2, Yin Bun Cheung1, Shungu Munyati3, Peter Godfrey-Faussett1, Richard Hayes1,
Gavin Churchyard1, Anthony Butterworth1,2, Peter Mason2,4
1 London School of Hygiene and Tropical Medicine, London, United Kingdom, 2 Biomedical Research and Training Institute, Harare, Zimbabwe, 3 National Institute of Health
Research, Harare, Zimbabwe, 4 Department of Medical Laboratory Sciences, University of Zimbabwe, Harare, Zimbabwe
Funding: This study was funded by
the Wellcome Trust. The funders had
no role in the design, data collection
and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors
have declared that no competing
Academic Editor: Mario Raviglione,
Stop TB-World Health Organization
Citation: Corbett EL, Bandason T,
Cheung YB, Munyati S, Godfrey-
Faussett P, et al. (2007)
Epidemiology of tuberculosis in a
high HIV prevalence population
provided with enhanced diagnosis
of symptomatic disease. PLoS Med
4(1): e22. doi:10.1371/journal.pmed.
Received: May 10, 2006
Accepted: October 30, 2006
Published: January 2, 2007
Copyright: ? 2007 Corbett et al.
This is an open-access article
distributed under the terms of the
Creative Commons Attribution
License, which permits unrestricted
use, distribution, and reproduction
in any medium, provided the
original author and source are
Abbreviations: CI, confidence
interval; DOTS, directly observed
treatment short course; IRR,
incidence rate ratios; OR, odds ratio;
fraction; TB, tuberculosis; TST,
tuberculin skin test; VCT, voluntary
counselling and HIV testing; WHO,
World Health Organization
* To whom correspondence should
be addressed. E-mail: elc1@mweb.
A B S T R A C T
Directly observed treatment short course (DOTS), the global control strategy aimed at
controlling tuberculosis (TB) transmission through prompt diagnosis of symptomatic smear-
positive disease, has failed to prevent rising tuberculosis incidence rates in Africa brought
about by the HIV epidemic. However, rising incidence does not necessarily imply failure to
control tuberculosis transmission, which is primarily driven by prevalent infectious disease. We
investigated the epidemiology of prevalent and incident TB in a high HIV prevalence
population provided with enhanced primary health care.
Methods and Findings
Twenty-two businesses in Harare, Zimbabwe, were provided with free smear- and culture-
based investigation of TB symptoms through occupational clinics. Anonymised HIV tests were
requested from all employees. After 2 y of follow-up for incident TB, a culture-based survey for
undiagnosed prevalent TB was conducted. A total of 6,440 of 7,478 eligible employees
participated. HIV prevalence was 19%. For HIV-positive and -negative participants, the
incidence of culture-positive tuberculosis was 25.3 and 1.3 per 1,000 person-years, respectively
(adjusted incidence rate ratio ¼ 18.8; 95% confidence interval [CI] ¼ 10.3 to 34.5: population
attributable fraction ¼ 78%), and point prevalence after 2 y was 5.7 and 2.6 per 1,000
population (adjusted odds ratio ¼ 1.7; 95% CI ¼ 0.5 to 6.8: population attributable fraction ¼
14%). Most patients with prevalent culture-positive TB had subclinical disease when first
Strategies based on prompt investigation of TB symptoms, such as DOTS, may be an
effective way of controlling prevalent TB in high HIV prevalence populations. This may translate
into effective control of TB transmission despite high TB incidence rates and a period of
subclinical infectiousness in some patients.
The Editors’ Summary of this article follows the references.
PLoS Medicine | www.plosmedicine.org January 2007 | Volume 4 | Issue 1 | e220164
P PL Lo oS S MEDICINE
Tuberculosis (TB) disease can result from either rapidly
progressive disease following recent infection with Mycobacte-
rium tuberculosis or from reactivation of latent TB infection.
Reactivational disease predominates in countries that have
achieved good control of transmission, but most disease in
endemic countries is due to recently transmitted infection
. Accordingly, directly observed treatment short course
(DOTS), the TB control strategy of the World Health
Organization (WHO), aims to reduce the burden of prevalent
smear-positive TB through prompt diagnosis and effective
treatment of symptomatic patients with infectious disease .
In theory, successfully reducing point prevalence will lead to
falling TB incidence rates as TB transmission goes into
decline (see Box 1) . DOTS has had notable success in a
number of countries with low HIV prevalence, and world-
wide, it is considered one of the most cost effective of all
health interventions .
Trends are very different in Africa, however, with the HIV
epidemic driving rapid increases in TB case-notification rates
despite implementation of DOTS [3,4]. A pressing and
undetermined question is whether or not DOTS has also
failed to contain TB transmission rates [4,5]. This cannot be
assumed, as TB incidence would be expected to rise during
the course of an HIV epidemic, even if TB transmission rates
were in decline, simply because of increased numbers of
highly susceptible individuals .
Prevalent infectious TB is the direct source of TB trans-
mission events (Box 1). Evidence from South African gold
miners suggests that a DOTS-based approach successfully
controlled prevalent TB during a severe epidemic of HIV and
HIV-related incident TB . These divergent trends between
prevalence and incidence were ascribed to much more rapid
self-presentation of HIV-related TB, and offer hope that TB
transmission rates were also contained . However, gold
miners are unusual because of occupational exposure to silica
dust, and although the point prevalence of TB was stable, it
was high in both HIV-positive and HIV-negative subpopula-
tions . Also, studies among HIV-positive persons attending
for voluntary counselling and testing and in home-based HIV/
AIDS care patients have consistently reported high rates of
undiagnosed prevalent TB [6–8].
HIV on the point prevalence and incidence of TB, and to
investigate the extent to which infectious (culture-positive)
population. For logistical and ethical reasons, the study was
nested within a cluster-randomised trial comparing two
different strategies of providing voluntary counselling and
HIV testing (VCT) at 22 different workplaces in Harare,
Zimbabwe. Company clinics were the unit of randomisation,
and both VCT strategies were linked to the same package of
basic HIV care, including isoniazid preventive therapy for
Study Participants and Cohort Follow-Up
Twenty-two small and medium-sized enterprises (100 to
600 employees) in Harare were enrolled between September
2001 and July 2002, and followed up for 2 y at each site. Most
were manufacturers. None involved exposure to silica dust or
other occupational risk factors for TB, and none provided
accommodation. All employees were asked to consent to a
baseline questionnaire including questions about smoking,
previous TB treatment, and household contact, and to
provide blood for HIV testing, with written informed
consent. There was no active screening for TB symptoms or
disease at enrolment, but employees were informed that
diagnosis and management of common adult illnesses,
including HIV and TB, could be obtained through their
occupational clinic. VCT was available for workers wishing to
know their HIV status. Companies were randomly allocated
to either company clinic or voucher-based VCT in a cluster-
randomised study . Payrolls were checked every 3 mo for
loss to employment and new employees.
Company clinics were provided with a project nurse
trained in integrated management of common adult illnesses,
adapted from WHO guidelines . Patients presenting with
cough for 3 wk or more were investigated with three sputum
smears and cultures, including one early morning specimen
(‘‘spot-morning-spot’’), followed by repeat specimens and
chest radiography if symptoms persisted after broad-spec-
trum antibiotics. Employees diagnosed with TB outside the
project were asked to report to their project nurse and
provide three sputum specimens for smear and culture, with
the incentive of household screening. We monitored employ-
er TB notifications, routinely sent by the Environmental
Health Department of Harare City Health to notify employ-
ers of TB if a workplace address is provided by the patient on
registration, and screened workers retiring because of ill
health, or off sick for more than 2 wk.
Workers testing HIV positive by VCT were provided with
basic HIV care including cotrimoxazole (if in WHO stages 2
to 4) and isoniazid preventive therapy for 6 mo (if the TST ?
5 mm, or if previously treated for TB . 2 y earlier) .
Active TB was excluded (symptom screening, with chest
radiography and TB smears and cultures if symptomatic)
immediately before starting isoniazid. (HIV-positive employ-
ees were not otherwise routinely screened for tuberculosis.)
Antiretroviral therapy (ART) was not widely available in
Zimbabwe at the time of this study and was not provided,
although referral was made to outside providers.
After 2 y, each workforce was screened for TB using
symptoms (cough, fever, hemoptysis, night sweats, and
Box 1: Definitions of Prevalent and Incident TB as Used in
Point prevalence of TB: the fraction of people surveyed at any
given point in time with active TB (here given as the number of
cases per 1,000 population). In this study, patients on TB
treatment were not considered to have active TB unless they
were culture positive.
Incidence of TB: the rate at which TB develops over time (here
given as the number of cases per 1,000 person-years).
Determining incidence requires longitudinal (cohort) studies,
whereas cross-sectional (prevalence) surveys are used to
PLoS Medicine | www.plosmedicine.org January 2007 | Volume 4 | Issue 1 | e220165
Epidemiology of TB in Harare
unintentional weight loss) and TB cultures. Three sputum
specimens were collected from all participants. Smears and
cultures were processed immediately for participants with
one or more symptoms. For asymptomatic participants, a
single pooled specimen was cultured, with storage of three
smears for reading if the pooled culture was positive.
Concentrates were stored at ?20 8C, and retrieved for
redecontamination and repeat culture in case of initial
culture contamination. Confidential HIV tests were re-
quested, with the option of VCT. TB suspects (symptoms or
positive screening culture) had repeat sputum microscopy,
culture, and chest radiography, and were followed until TB
was confirmed or excluded.
TB Case Definitions
Incident TB. Definite TB was defined as compatible illness
plus positive smear or growth of M. tuberculosis from two or
more sputum specimens, or positive smear or growth of M.
tuberculosis from one specimen with suggestive radiological
abnormalities and response to TB treatment.
Probable TB was defined as compatible illness with
response to TB treatment following failure to respond to
broad-spectrum antibiotics. Suspected pulmonary, pleural, or
miliary TB was confirmed by radiological response. Radio-
graphs were read by two independent readers. Other forms of
extrapulmonary TB were confirmed by clinical response
(weight gain and resolution of symptoms within 2 mo).
A number of patients were diagnosed and started on TB
treatment by outside providers. TB clinic records, sputum
smear results, and radiographs were used to apply case
definitions, but cultures were not usually obtained before
treatment was started. For the purposes of analysis, we have
assumed that such patients were culture positive if smear
positive, and culture negative if smear negative.
Prevalent TB. Case definitions could not be met on the
basis of prevalence screen results alone: additional evidence
of TB from follow-up investigations was required, such as
confirmatory positive smears or cultures, or radiological
evidence of TB. Patients taking TB treatment were not
considered to have active TB unless they were still culture
positive. Screening (not follow-up) results defined smear and
culture status for the point prevalence estimates.
Definite TB was defined as growth of M. tuberculosis from
two or more sputum specimens, or from one specimen
together with suggestive radiological abnormalities.
Probable TB was defined as compatible radiological
features, with response to TB treatment within 2 mo
following failure to respond to broad-spectrum antibiotics.
Decontamination with 4% NaOH and Lowenstein-Jensen
(LJ) slopes were used for TB culture. M. tuberculosis was
speciated by colonial morphology and failure to grow at room
temperature and at 45 8C, and on PNB-containing LJ slopes.
Both negative and positive controls were routinely included
in each batch of cultures. Concentrated smears were stained
with auramine O and read by fluorescence microscopy by two
readers. Only smears subsequently confirmed with Ziehl-
Neelsen staining were reported as positive.
Confidential HIV serology used Determine (Abbott Diag-
nostics, http://www.abbottdiagnostics.com), with all positives
and 10% of negative specimens being confirmed by Unigold
(Trinity Biotech, http://www.trinitybiotech.com) for serum
specimens. Dried blood spots or oral mucosal transudate
were collected from participants not willing to provide serum,
and were tested using Determine/Vironostika and OraQuick/
Vironostika (OraQuick, Abbott Diagnostics; Vironostika,
bioMe ´rieux, http://www.biomerieux.com), respectively.
Approval was granted by the Ethics Committees of the
London School of Hygiene and Tropical Medicine, Biomed-
ical Research and Training Institute, Harare, Zimbabwe, and
Medical Research Council of Zimbabwe, Harare, Zimbabwe.
Written informed consent was provided by all participants.
All information obtained from participants was kept con-
fidential. Individual medical records were stored in locked
cupboards at the respective company clinics. At the end of
the study period, medical records were made available to
remaining clinic staff, if shared confidentiality was requested
by the employee, to enable ongoing care; otherwise medical
records were removed.
Data were captured using EpiInfo 2002 (Centers for Disease
Control and Prevention, http://www.cdc.gov/EpiInfo) and
analyzed with Stata 7.0 software (http://www.stata.com).
Follow-up of each workforce started when TB diagnosis
became available at company clinics and continued for 2 y.
Follow-up for any given employee was from the later of either
the date that workforce follow-up started or the date of
joining the workforce, until the earlier of either the date that
workforce follow-up stopped or the date of leaving the
workforce. The prevalence survey started the day after follow-
up finished at each site, and so prevalent cases were not
included in the incident cohort analysis. Sixty-one partic-
ipants were HIV negative at baseline, but HIV positive at the
prevalence survey. None had incident or prevalent TB. Their
data are analyzed as HIV negative for the incidence cohort
and HIV positive for the prevalence survey.
Poisson regression and logistic regression were used for
multivariate analysis of the cohort and cross-sectional data,
respectively. Adjusted odds and rate ratios were used to
calculate adjusted population-attributable fractions (PAFs)
. Robust confidence intervals (CIs) were used to adjust for
clustering by site. Bootstrapping was used to calculate 95%
confidence limits for disease duration estimates based on the
ratio of prevalence and incidence of TB, and for disease
duration ratios .
Participation rates are shown in Figure 1. Baseline
characteristics of the 6,440 participants are shown by HIV
status in Table 1. HIV prevalence was 19%. HIV-positive
workers were more likely to have been treated for TB in the
past (11% versus 2%, p ¼ 0.027), to have had household
contact with a TB patient (22% versus 15%, p , 0.001), and to
be middle aged (p ¼ 0.01). They were also more likely to be
current or former smokers and to be manual workers (p ,
0.001 for both). Workforce turnover was higher for HIV-
positive than HIV-negative workers, with 69% and 78%,
respectively, remaining in the workforce at the end of follow-
up (p , 0.001).
PLoS Medicine | www.plosmedicine.org January 2007 | Volume 4 | Issue 1 | e22 0166
Epidemiology of TB in Harare
Incidence of TB Disease
A total of 106 patients with definite or probable TB
occurred during cohort follow-up, of whom 61 (58%) were
smear or culture positive. An additional 11 patients were
treated for TB that did not meet case definitions. Overall TB
incidence was 9.9 (95% CI ¼ 7.8 to 12.9) per 1,000 person-
years follow-up for all definite and probable disease. A
breakdown of incidence rates by HIV status and smear and
culture category is shown in Table 2 and Figure 2. Univariate-
and multivariate-adjusted incidence rate ratios (IRRs) and
PAFs for all TB cases and for culture-positive TB disease are
shown in Table 3.
Incidence and risk factors for culture-positive TB disease.
The incidence of culture-positive TB was significantly higher
in HIV-positive than HIV-negative participants (overall rates,
25.3 and 1.3 per 1,000 person-years follow-up, respectively;
univariate IRR ¼ 20.0 (95% CI ¼ 10.5 to 38.0). Previous TB
treatment (IRR¼3.6; 95% CI¼1.9 to 6.9), male sex (IRR¼4.0;
95% CI¼0.9 to 17.8), being a current or former smoker (IRR
¼ 1.9; 95% CI ¼ 1.2 to 3.0), older age (IRR ¼ 1.2 per group
above 16 to 24 y; 95% CI¼1.1 to 1.3), manual job type (IRR¼
1.3; 95% CI ¼ 1.04 to 1.6), and having been a household
contact of a TB patient (IRR ¼ 2.3; 95% CI ¼ 1.1 to 5.0) were
each significantly associated with an increased rate of culture-
However, there was considerable confounding by HIV, and
on multivariate analysis, only HIV (adjusted IRR ¼ 18.8; 95%
CI¼10.3 to 34.5) and male sex (adjusted IRR¼4.4; CI¼1.0 to
19.8) remained significant (Table 3). Adjusted PAFs are also
shown in Table 3, with the highest fractions (78% and 75%,
respectively) being for HIV infection and male sex.
Prevalent TB Disease
A total of 4,668 cohort participants (874 HIV positive and
3,794 HIV negative) were screened for prevalent TB at the
end of follow-up. The participation rate for employees
remaining in employment was 96%. Active TB was detected
in 27 participants, giving a workforce point prevalence of 5.8
per 1,000 for all TB, and 3.2 and 1.3 per 1,000 for culture-
positive and smear-positive TB, respectively.
A breakdown of prevalence by HIV status and smear and
culture category is shown in Table 2 and Figure 2. A high
proportion of patients with prevalent TB had subclinical
disease at the time of screening, with 11 (41% of all prevalent
cases and 73% of culture-positive cases) detected only
Figure 1. Study Profile
HIV-ve, HIV negative; HIVþve, HIV positive.
Table 1. Baseline Characteristics
Category CharacteristicHIV Positive, n (%)HIV Negative, n (%)p-Value
Number of cohort study participants
Age group (y) (p ¼ 0.01)a
16 to 24 y
25 to 29 y
30 to 34 y
35 to 39 y
40 to 49 y
50 y or older
Previously treated for TB
Company clinic offering rapid testing on-site
Had VCT during course of follow-up
Received isoniazid preventive therapy
Received antiretroviral therapy (outside provider)
Previous household contact with TB patient
Job type (p ,0.001)
aData missing for one HIV-positive and two HIV-negative participants.
bData missing for four HIV-positive and eight HIV-negative participants.
NA, not applicable.
PLoS Medicine | www.plosmedicine.org January 2007 | Volume 4 | Issue 1 | e220167
Epidemiology of TB in Harare
through screening culture. Symptoms had developed in all
but two by follow-up.
Univariate- and multivariate-adjusted odds ratios (ORs) are
shown in Table 3, together with PAFs for variables included
in the multivariate models. HIV infection was a significant
risk factor for prevalent TB (unadjusted OR ¼ 4.1; 95% CI ¼
1.9 to 8.9), as were smoking (unadjusted OR ¼ 3.6; 95% CI ¼
1.5 to 8.8), and older age (unadjusted OR ¼ 1.2 per category
above 16 to 24 y; 95% CI¼1.05 to 1.4). Previous TB treatment
was not a significant risk factor for prevalent TB in either
univariate or multivariate analysis (PAF ¼ 3% in both
Risk factors for prevalent culture-positive TB disease.
Statistical power was limited by the small numbers, but there
were no significant risk factors for prevalent culture-positive
TB. The adjusted odds ratio and PAF for HIV infection were
1.7 (95% CI ¼ 0.5 to 6.8) and 14%, respectively.
Duration of disease before TB diagnosis. The ratio of
prevalent to incident TB provides an estimate of mean
duration of disease before diagnosis (a measure of the case-
detection rate) . Precision was limited by small numbers,
but duration was significantly shorter for HIV-related TB,
with mean duration of smear positivity of 6 wk, and of 12 wk
for culture positivity. This compares with 53 and 108 wk,
respectively, for HIV-negative TB. The ratio of duration for
HIV-positive compared to HIV-negative TB was 0.12 (95% CI
¼ 0 to 0.70) for smear positivity and 0.11 (95% CI ¼ 0.02 to
0.37) for culture positivity (Table 4).
Effect of VCT, Isoniazid Preventive Therapy, and HIV Care
on TB Epidemiology
In addition to facilitated diagnosis, employees were
provided with VCT linked to isoniazid preventive therapy.
A total of 403 (33%) HIV-positive workers had VCT during
the course of the study, and so became eligible for HIV care,
and 75 (6% of all HIV-infected employees) received isoniazid.
The main factor limiting isoniazid delivery was a low rate of
tuberculin positivity (25% of TST-tested HIV-positive par-
ticipants), as reported elsewhere in Africa [13–15]. TB was
diagnosed in eight employees (9% of all incident TB cases in
HIV-positive employees) as the result of preisoniazid screen-
ing. The potential impact of the HIV care program on
incident and prevalent TB was, therefore, limited (employees
were not screened for active TB unless they were TST positive
Table 2. TB Incidence Rates (per 100,000 Person-Years Follow-Up), TB Point Prevalence per 100,000 Population, and HIV Rate Ratios for
Incident and Prevalent TB
Category ResultOverall Ratea
HIV PositiveHIV Negative HIV IRR/ORc
Incident TB Smear-positive TB
All definite/probable TBd
All definite/probable TB
All definite/probable TB
Symptomatic at time of screene
aRates per 1,000 person-years follow-up for incident TB, and per 1,000 population for prevalent TB.
bNumber of TB cases. Denominators are 1,976 and 8,682 person-years follow-up for HIV-positive and HIV-negative incidence rates, respectively, and 874 HIV-positive and 3,974 HIV-
negative participants in the prevalence survey.
cIRR for incident TB, and OR for prevalent TB.
dDiagnosisof TBwas madeby health care providersoutsidetheproject for 38(44%) and five(25%) ofHIV-positiveand HIV-negativeTB patients,respectively.In thesecases, TB cultureswere
usually not taken until treatment had been started. Because of this, 13 HIV-positive patients with smear-positive TB were not culture confirmed, but are assumed to have been culture
positive,and 24 HIV-positiveand fiveHIV-negativepatients withsmear-negativeTB didnot haveculturestaken beforestarting TB treatment and areassumedto havebeen culturenegative.
eAll participants were screened for TB symptoms and by TB culture at the time of the prevalence survey. Smear, culture, and symptom status reflect screening results only, and do not
reflect symptoms reported or bacteriological results obtained on subsequent follow-up. Seven participants with growth of M. tuberculosis on screening cultures are not included as cases,
because there was no evidence of disease on follow-up. One asymptomatic participant was found to have TB after a scanty growth of M. avium complex on screening culture. Follow-up
cultures grew M. tuberculosis. This has been classified as asymptomatic smear and culture-negative TB at the time of screening.
Figure 2. Point Prevalence and Annual Incidence Rates for Smear-
Positive and Culture-Positive TB, According to HIV Status
Columns are divided into smear-positive (dark portion) and smear-
negative culture-positive TB (light portion).
PLoS Medicine | www.plosmedicine.orgJanuary 2007 | Volume 4 | Issue 1 | e22 0168
Epidemiology of TB in Harare
or otherwise eligible for isoniazid) and is not considered here
because of the statistical complexities of including an
intervention delivered through a cluster-randomised trial
design. Similarly, antiretroviral therapy is known to affect TB
incidence , but was only accessed by 21 employees during
this study, and so is not considered in the analysis.
The results of this study suggest that passive case finding
and treatment, the cornerstone of global TB control, may still
be an effective way to control prevalent TB in high HIV
prevalence populations, even when control of TB incidence
has been apparently unsuccessful. This has major implica-
tions for TB control prospects, as it supports an approach
whereby DOTS retains the essential role of controlling TB
transmission rates, with the addition of integrated HIV/TB
care aimed at providing individual protection from the very
high risks of TB morbidity and mortality that are a striking
feature of HIV disease in TB endemic areas . The overall
point prevalence of smear-positive TB after 2 y of easy access
to diagnosis was 1.3 per 1,000 population in this study. This is
considerably lower than most other reports of adult and
whole-population point prevalence estimates from Africa
[5,17–25] and Asia [26–34], and below the burden in Africa
 in the pre-TB treatment era (Figure 3). Although this may
in part reflect a ‘‘healthy worker’’ effect in this study, the high
HIV prevalence of 19%, our inclusion of all employees who
were on sick-leave during the prevalence survey, and the high
TB incidence rates argue against this as the sole effect. Of
note, our study population was predominantly male and
middle-aged, both of which are strong risk factors for
prevalent TB disease in other settings [26–29].
A low point prevalence of infectious TB is likely to be
associated with low TB transmission rates. In this respect, the
very low point prevalence of symptomatic infectious TB (0.9
per 1,000 population for culture-positive TB) is also notable.
Symptomatic TB disease developed within a few weeks in all
but two of the initially asymptomatic patients detected
through the prevalence survey. Patients with subclinical TB
have been consistently reported from previous prevalence
surveys [27,30,35,36], and present a particular challenge to
delivery of preventive therapy because they are at high risk of
being inadvertently considered disease-free and so started on
preventive therapy, usually a single drug. The high propor-
tion of subclinical cases in this prevalence survey may reflect
the unusually good access to investigation of TB symptoms
with sensitive smears and culture. Infectiousness may be low
in relatively asymptomatic patients, since coughing is
important in TB transmission, and so control of secondary
TB transmission events may be even better than is implied by
the overall point prevalence estimates.
The results of this study are consistent with our previous
finding in South African gold miners that HIV has a less
pronounced impact on the point prevalence of active TB
disease than on TB incidence rates, at least in the context of
ready access to diagnosis of symptomatic TB . The standard
finding among HIV-negative persons that the burden of
prevalent TB disease exceeds the annual TB incidence rate
was reversed among our HIV-positive participants (Figure 2).
This may be an intrinsic feature of HIV-related TB, due to
rapid progression of TB disease and early onset of symptoms
resulting in more rapid case finding as the duration of disease
before diagnosis was significantly shorter for HIV-positive
Table 3. Risk Factors for Incident and Prevalent TB: Multivariate-Adjusted IRRs and ORs, and Population Attributable Fractions
Category Risk FactorIncident TBPrevalent TB
Unadjusted Adjusteda(95% CI)Unadjusted Adjusted (95% CI)
Previous TB treatment
Household TB contact
Previous TB treatment
Household TB contact
1.6 (0.9 – 2.7)
All TB cases
aAlso adjusted for clustering by site and for isoniazid preventive therapy use.
bPAF ¼ population-attributable fractions for the multivariate-adjusted model of incident tuberculosis.
cPAF2 ¼ population-attributable fractions for the multivariate-adjusted model of prevalent tuberculosis.
Table 4. Indirect (Point Prevalence Divided by Incidence)
Estimates of Duration of Infectiousness before Diagnosis of TB
Disease, According to HIV Status
Duration (95% CI)Duration
HIV Positive HIV Negative
6 (0–17) wk
12 (3–25) wk
18 (9–30) wk
53 (9–159) wk
108 (44–263) wk 0.11
83 (40–172) wk 0.21
Values given are mean duration of disease before diagnosis.
aDuration in HIV-positive TB patients divided by duration in HIV-negative patients.
PLoS Medicine | www.plosmedicine.org January 2007 | Volume 4 | Issue 1 | e22 0169
Epidemiology of TB in Harare
than HIV-negative TB patients in this and in the South
African study . Future studies are now needed to establish
whether this relationship holds when access to diagnosis is
more limited, and whether it can be replicated without use of
culture and sensitive microscopy as first-line investigations.
As in South Africa , most patients in this study with
prevalent smear- or culture-positive TB were HIV negative,
and overall point prevalence predominantly reflected control
in the HIV-negative subpopulation. In the current study, only
33% of patients with prevalent culture-positive TB were HIV
positive compared to 82% of those with incident culture-
positive TB, and the adjusted PAFs for HIV were much lower
for prevalent than incident culture-positive TB (14% and
78%, respectively). Prevalent smear-positive TB is the
primary driving force of TB transmission, and the finding
that the impact of HIV on prevalent smear-positive TB is
relatively modest is consistent with the finding that DOTS
appears to have been more successful in controlling TB
transmission than TB incidence rates in some high HIV
prevalence countries [37–39].
The HIV diagnosis and care provided during the study may
have contributed to rapid diagnosis of TB. Once diagnosed,
HIV-positive workers were offered regular 3-monthly follow-
up, and were treated for latent TB infection if they were
tuberculin positive. However, only 23% of HIV-positive TB
patients had VCT before their TB diagnosis, and TB
incidence rates remained high despite the intervention. This
was anticipated . We have not considered the effects of
isoniazid preventive therapy, administered during the course
of the study, or antiretroviral therapy, because of the low
coverage and complexity of adjusting for these effects. One
other limitation is that capture of incident TB cases may have
been incomplete, so that TB incidence may have been
The power to identify risk factors for prevalent TB was
limited by the success of the intervention, leading to low
point prevalence, but HIV infection and smoking were of
borderline significance on multivariate analysis when all TB
cases (including culture negative) were included. Smoking has
been identified as an important cause of morbidity and
mortality from TB in India , but in this study the effect of
smoking was less marked and was nonsignificant once
adjustment for confounding with HIV status was made.
Previous TB treatment, a major risk factor for prevalent TB
disease in the pre-DOTS era , was not a significant risk
factor for prevalent TB disease in this population, although
we relied on self-reporting and so may have had incomplete
In summary, we have demonstrated that a strong program
based on case finding and treatment of self-presenting TB
patients was associated with a burden of prevalent infectious
TB disease well below annual TB incidence rates in this high
Figure 3. Adult and Whole Population Estimates of the Point Prevalence of Infectious TB Disease (per 100,000 Population) in Africa and Asia
Bars are divided into smear-positive (dark portion) and smear-negative culture-positive TB (light portion). Not all studies used cultures, so only the
prevalence of smear-positive disease is shown for these. Italic text indicates the current study results (HIV-positive participants, HIV-negative
participants, and overall symptomatic burden). Otherwise, data were extracted from references [5,17–25] (Africa) and [26–34] (Asia). Ranking is by point
prevalence of smear-positive disease. Whole-population estimates are typically 30%–50% lower than adult point prevalence estimates, because point
prevalence of TB is negligible in children. Adult prevalence is shown whenever possible.
* Methodology varied, but studies in which asymptomatic participants were screened for disease are included in the top half of the graph, whereas the
bottom half shows results from studies in which only participants reporting one or more TB symptoms were screened further, with comparable results
for symptomatic TB from the current study.
PLoS Medicine | www.plosmedicine.org January 2007 | Volume 4 | Issue 1 | e220170
Epidemiology of TB in Harare
HIV prevalence population. Most patients with prevalent
smear- or culture-positive TB were HIV negative and
asymptomatic at the time of screening, as previously reported
from a similar study in South Africa . This underscores the
importance of including HIV-negative individuals in intensi-
fied TB control efforts. There has been a growing consensus
that efforts to control TB in Africa need to be intensified
[4,43,44]. The new global TB control strategy, the Global Plan
to Stop TB 2006–2015, emphasises the need to apply existing
diagnostic techniques, such as culture and sensitive micro-
scopy techniques as used in this study, as well as the need to
develop new diagnostic tools and expand joint TB/HIV
activities . Mathematical modelling suggests that better
case finding and treatment for infectious TB will be among
the most effective and cost-effective interventions [45,46].
Given the already brief duration of HIV-related TB disease
before self-presentation, the added value of routine periodic
screening for asymptomatic TB among known HIV-positive
persons needs to be determined [4,43]. It will also be
important to investigate the impact of antiretroviral therapy
on the subclinical period of infectiousness among HIV-
positive TB patients . If generalisable, the current study
results imply that well-implemented, intensified case finding
and treatment may prove capable of reducing TB incidence
in high HIV prevalence settings in the long term, despite the
disappointing short-term response [4,44], if applied widely
and intensively enough to maintain low levels of prevalent
infectious TB for a sufficiently prolonged period.
ELC had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the
data analysis. We thank the project nurses, data and laboratory teams,
and all participants. Harare City Health managed the TB patients and
provided access to records and radiographs required for TB case
Author contributions. ELC, SM, RH, GC, and AB designed the
study. ELC, TB, YBC, SM, PGF, RH, and AB analyzed the data. ELC,
TB, YBC, SM, PGF, RH, GC, AB, and PM contributed to writing the
paper. PM was responsible for all of the laboratory data and for
ethical approval and monitoring of ethical issues regarding patients.
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Background. Around eight million people develop tuberculosis (TB)
disease every year and of these nearly two million die. However, many
more people are infected than have symptoms; perhaps one-third of the
world’s population is currently infected with TB. Most people infected
with TB have what is termed ‘‘latent infection,’’ or in other words they
are infected with the bacterium but do not experience any symptoms of
disease. Individuals infected with TB who also have a weakened immune
system, for example through HIV/AIDS, are much more likely to develop
TB disease. In some regions HIV is very common—for example,
approximately 11% of sub-Saharan African adults are HIV positive—
and because of this cases of TB disease have risen substantially as HIV
spreads. The Word Health Organization has a recommended interna-
tional strategy for control of TB called ‘‘DOTS’’ (Directly Observed
Therapy, Shortcourse). Among the five main elements of DOTS are
mechanisms for promptly diagnosing and treating people who have TB
disease. It is hoped that this strategy will help to reduce the number of
new cases of TB diagnosed each year, because individuals promptly
diagnosed and treated will then be less likely to transmit the disease to
Why Was This Study Done? In this study the investigators wanted to
find out if intensive DOTS, combined with giving people better access to
test facilities to diagnose TB disease, could be effective in reducing the
spread of TB from one person to another in Africa. It is not clear whether
DOTS alone can control the spread of TB in populations with high
numbers of HIV-positive people already infected with TB and so at high
risk of going on to develop TB disease. Specifically, they wanted to
collect data on the number of new TB cases being diagnosed per year
and how that related to the proportion of the overall population that
had infectious undiagnosed TB at any given point in time. They also
wanted to find out whether providing good access to services for
diagnosis and treatment of TB would affect either the number of new TB
cases or the proportion of a given population that had infectious
What Did the Researchers Do and Find? This research study was
carried out as part of a trial in which two different strategies for
providing testing and counseling for HIV in the workplace were being
compared. The trial took place within 22 companies in Harare,
Zimbabwe, where HIV is very common in the adult population. Along
with HIV testing and counseling, the trial provided for close follow-up
and testing of anyone presenting with TB-like symptoms, with the aim of
detecting as many cases in the population as possible. At the end of the
two-year period, all workers were checked for undiagnosed TB disease,
and cultures were carried out to find out how many of these people had
infectious TB (but who might not necessarily have had symptoms). 6,440
workers were recruited into the study, of whom 19% were HIV positive.
During the period of follow-up, 106 cases of TB were seen, and HIV-
positive workers were far more likely than HIV-negative workers to
experience TB disease. At the end of the study, 4,668 workers were
checked for the presence of undiagnosed TB and 27 individuals were
found to be affected, but not all of these people experienced any
symptoms of disease.
What Do These Findings Mean? At the end of this study, the
proportion of workers found to have undiagnosed TB was fairly low—
lower than the level found in other studies carried out in other parts of
the world with a high burden of TB disease but low burden of HIV. The
researchers therefore concluded that the systems set up within the trial
(for close follow-up and testing for TB disease) were an effective way of
controlling the overall proportion with infectious TB, even though HIV
infection rates were also high. This is likely to mean that the spread of TB
infection to others—a prerequisite for achieving TB disease control—was
also well controlled. However, more intensive efforts to reduce the risk of
TB disease in HIV-positive Africans already infected with TB are also
needed, although this study did not aim to find out about the impact of
Additional Information. Please access these Web sites via the online
version of this summary at http://dx.doi.org/10.1371/journal.pmed.
? Information from the World Health Organization on DOTS, the
internationally recommended TB control strategy; a factsheet on TB
is also available
? The STOP TB Partnership is an international initiative involving several
agencies seeking to combat the rise of tuberculosis
? The US National Institute of Allergy and Infectious Diseases also
publishes a factsheet for patients
? US Centers for Disease Control, information for patients and
professionals about TB
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Epidemiology of TB in Harare