The ART-LINC collaboration
Incidence of tuberculosis in antiretroviral treatment programs in lower-income
countries: Impact of screening and diagnostic capacity.
Draft 1.0
Target: Clinical Infectious Diseases
Brief Report
(1500 words max)
We examined screening, diagnostic and treatment practices regarding TB in 24 ART
programs from lower income countries. In suspected TB, chest X-ray (CXR), sputum
examination and culture were available free of charge to patients in 21 (87.5%), 22
(91.7%) and 16 (66.7%) sites, respectively. Treatment was rifampin based at all sites, 4
(18.7%) used directly observed therapy (DOT) during the first 2 months and 6 (25%)
during the entire treatment period. INH prophylaxis was routinely used in 6 sites (25%).
The TB rate was 8.2 per 100 pyrs (95% CI 7.7 to 8.7) during the first year of ART. It was
12.4 in programs routinely screening for TB compared to 4.8 per 100 pyrs in programs
not screening (adjusted rate ratio 0.39, 95% CI 0.20-0.79). Low baseline CD4 count
were strongly associated (p<0.001) with a higher risk of TB in sites with access to chest
X-rays (CXR), sputum and culture, but not in sites with more limited diagnostic
capabilities. Only a minority of sites participating in this network routinely screen for TB
before and during ART, and only half of programs use DOT. More intensive screening for
TB may substantially improve case detection and might contribute to reducing the high
early mortality observed in patients starting ART in low income countries.
Introduction
Although HAART reduces death rates remarkably from all causes, the management of
tuberculosis (TB)
and
other
opportunistic infections (OIs)
remains an
essential
component of comprehensive HIV care. Nowadays, TB continues to cause morbidity and
mortality in HIV-infected individuals since some HAART patients do not have a sustained
response to antiretroviral agents for multiple reasons such as poor adherence, drug
toxicities, drug interactions and initial acquisition of a drug-resistant strain of HIV1.
Furthermore, the Starting Antiretrovirals at three Points in Tuberculosis (SAPIT) trial
revealed that mortality among TB-HIV co-infected patients is reduced substantially if ART
is provided with TB treatment 2 (what is the best ref?). An optimal scaling-up of
antiretroviral therapy thus cannot be performed without a successful management of TB,
including extended access to secondary prophylaxis, early diagnosis and affordable
treatments. Despite this, the optimal use of existing diagnostic tests is failing nowadays3,
resulting
in
missed
diagnosis.
Since
standard
Rifanpicin-based
treatments
have
acceptable cure rates, high mortality rates in patients with both HIV and TB have been
attributed those missed diagnosis4. Furthermore, HIV infection, negative sputum smear,
extrapulmonary TB (two TB presentations being common in HIV infection) have been
identified as main factors associated with diagnostic delay5. Thus, intensified case finding
and appropriate diagnostic tools are nowadays key for trying to prevent TB fatalities.
We examined screening, diagnostic and treatment practices regarding TB in ART
programs in lower income countries. We additionally assessed the impact of screening
and diagnostic practices on TB detection rate.
Material and methods
A cross-sectional survey was performed (December 2007 - April 2008) using an online
questionnaire written in English, translated to French and revised after pilot testing. ARTLINC treatment programs were invited to complete the questionnaire, which
comprehensively covered sites’ general practices regarding ART supply and HIV/AIDS
management, including TB screening, diagnosis, prevention and treatment. The webbased WHO Data Collector system6 was used. All ART-LINC sites (n=24) agreed to
participate to the survey and completed this web-based questionnaire.
For 15 programs routinely recording detected TB cases, the site-level information could
be linked to patient data prospectively collected after the start of ART (Botswana
[Gaborone], Brazil [Porto Alegre and Rio de Janeiro], Côte d’Ivoire [Abidjan], India
[Chennai], Kenya [Eldoret], Nigeria [Lagos], Malawi [Lilongwe], Morocco [Casablanca],
Senegal [Dakar], South Africa [Cape Town, Khayelitsha, and Soweto], Thailand
[Bangkok], and Uganda [Kampala]).
Patients aged ≥16 years with a known date of HAART start, a documented baseline CD4
cell count and who had not previously received antiretroviral therapy were eligible.
HAART was defined as any antiretroviral combination therapy that included ≥ 3 drugs. As
of a previously published study7, the end point was a new pulmonary or extrapulmonary
TB after HAART initiation, defined as a diagnosis of a TB episode at least 6 months after
the last TB episode8. Time was measured from the start of HAART and ended at
whichever of the following events occurred first: new TB event or death, last follow-up
visit, or month 12 after HAART onset. Incidence rates were calculated for the first year of
HAART (ref # 6 again).
Crude TB incidences and adjusted rate ratios for baseline CD4, age and sex were
computed according to the following sites characteristics: tuberculosis clinic as point of
entry in the facility; TB diagnostic tests (CXR, sputum smear and cultures) availability
and costs charged to patients or not; and routine TB CXR screening. To estimate the
adjusted relative rates of 1-year tuberculosis incidence, we applied Poisson regression
analyses with gamma-distributed random effects (xtpoisson procedure in Stata 10.0,
Stata Corp, College Station, TX). Two additional random effects models were performed
for a) sites performing routine active case identification through CXR screening and with
full free diagnostic capacities (free CXR, sputum and culture for M. tuberculosis) (n=6)
and b) sites without routine active case identification and partial diagnostic capacities
(charges applicable to CXR and/or sputum; cultures not available or available with
charges) (n=9). In those two models, the following patients-level variables were
considered (baseline CD4 cell count and TB prophylaxis). Sites-specific variables included
baseline population TB incidence9 and TB programme as important point of entry in
HAART clinics. Both models were adjusted for age, sex and first-line antiretroviral
regimen.
Matthias: I think it would be better to adjust models from table 1 and 2 with the same
covariates. It does not change anything anyway….
Results
Seven of 24 sites (29.2%) routinely did CXR to screen for TB before and during ART. In
suspected TB, CXR, sputum examination and culture were available free of charge to
patients in 21 (87.5%), 22 (91.7%) and 16 (66.7%) sites, respectively. All sites routinely
performing TB screening diagnosed TB cases using free CXR, sputum and cultures. In
those not routinely performing screening, 76% did free CXR, 90% free sputum and 40%
free cultures.
Treatment was rifampin based at all sites, 10 (41.6%) used directly observed therapy
(DOT) at least during the first 2 months or during the entire treatment period. INH
prophylaxis was routinely used in 6 sites (25.0%) only.
Eligible patients (n=19413) were included from the 15 sites routinely collecting data on
TB. The median year of HAART onset was 2005 (IQR 2004-2005). The median CD4 cell
count was 115 cells/µL (IQR 46-191). In the first year of HAART, 1081 tuberculosis
events were diagnosed during 13236 person-years of follow-up. The overall TB rate was
8.2 per 100 person-years (95% CI 7.7 to 8.7) during the first year of ART. TB rates
varied according to diagnostic and screening practices among sites (table 1). It was 12.4
per 100 person-years in programs routinely screening for TB compared to 4.8 in
programs not screening (adjusted rate ratio 0.39, 95% CI 0.20-0.79). Low baseline CD4
counts (p<0.001) and national TB incidence (p=0.001) were strongly associated with
higher TB rates in sites with unlimited and free access to chest X-rays, sputum and
culture, but not in sites with more limited diagnostic capabilities (Table 2).
Discussion
We examined TB screening, diagnostic and treatment practices regarding TB in 24 ART
programs in lower income countries and were able to relate programs screening and
diagnosis practices to actual TB rate in 15 sites. Only a minority of sites participating in
this network routinely screened for TB before and during ART, used DOT and routinely
performed INH prophylaxis. The estimated overall TB incidence rate (8.2 per 100 personyears) was comparable to the one previously found (7.4 cases per 100 person-years;
95% CI, 6.6-8.4) but significantly varied according to TB screening practices. Moreover,
well-established associations between variables such as baseline CD4 or baseline national
incidence rates and TB incidence rate were weak in sites not performing CHX TB
screening, those ones noteworthy having more limited diagnostic capabilities.
Conversely, those associations were strong among sites routinely performing free
screening and diagnostic tests.
Lower TB incidence rate and weak associations both suggest inappropriate TB case
detection in sites not routinely screening for TB and with limited diagnosis capacities,
potentially leading to a substantial amount of missed TB diagnoses. Indeed, lack of
sensitive TB case detection produces false negatives (i.e. unidentified TB cases) which
may bias rate ratio estimates toward the null. Since sites routinely doing CXR screening
actually performed exclusively free diagnostic tests (CXR, sputum and culture), it is
difficult to determine whether better case detection relied on laboratory capacities free of
charge alone or active case finding procedures such as CHR TB screening. However, TB
rates were negatively associated with tests unavailability or tests for which patients
incurred the fees.
Participating sites were heterogeneous and represented a convenience sample. As
previously mentioned (ref # 6 again), an important number of patients had to be
excluded because of missing data. Adjusted mortality rates were lower in sites with full
and free diagnostic capacities but did not reach statistical significance (RR = 0.65 (0.341.23) p=0.183). On the other hand, rates of follow-up losses tended to be higher in
those sites (RR = 1.98 (0.85-4.61) p=0.114). The generalizability of our results and their
effect on mortality are therefore uncertain, but this study clearly points significant
problems with TB prophylaxis, screening, diagnosis and treatment. In addition, improved
TB detection rates in this study were not attributable to better patients follow-up.
In the light of the results of SAPIT 10 (ref), more intensive screening for TB improves case
detection and might contribute to reducing the high early mortality observed in patients
starting ART in low income countries. Accurate TB diagnosis in HIV-infected patients
cannot always solely rely on sputum smear microscopy. Cultures play an important role
in smear negative and extrapulmonary TB diagnostics and are mentioned in algorithms
and recommendations allowing earlier initiation of TB treatment in HIV patients 11,
. In
12
addition, cultures are commonly considered as the closest gold standard from clinical
specimens13. However, sputum smear examination by light microscopy is the only
diagnostic test for tuberculosis available in many lower income countries that are most
affected by tuberculosis, although only 20-50% of tuberculosis cases are estimated to be
positive by this method14, this proportion being even lower in the setting of HIV infection.
Therefore, active TB screening using CXR and sputum cultures that have been proposed
for HIV patients15,16 are obviously not widely implemented yet.
Very little is being done by governments and cooperation agencies to develop laboratory
facilities in countries with a high OI-related burden, including TB. This neglect might be
short-sighted as it leaves many territories incapable of performing or culture-based
diagnosis or drug-resistance testing.
Table 1
Patients’ important points of entry in the facility
TB program
Other 2
TB Diagnostic tools
Chest X-rays
Free of charge
Charges applicable
Sputum
Free of charge
Charges applicable
Cultures
Free of charge
Charges applicable
Not available
CXR TB screening
Routinely
Not routinely
1 Adjusted for baseline CD4, age and sex
2
PMTCT, STI clinic, VCT, spontaneous referral
n
%
Crude TB incidence
rate / 100 personyears (95% CI)
IRR (95% CI) 1
7
8
46.7
53.3
9.9 (5.0-19.7)
6.2 (2.7-14.1)
1.0
0.62 (0.22-1.72)
13
2
86.7
13.3
9.3 (5.1-17.2)
4.9 (3.0-8.1)
1.0
0.55 (0.26-1.18)
14
1
93.3
6.7
9.0 (5.1-15.8)
3.4 (2.7-4.4)
1.0
0.42 (0.23-0.74)
8
3
4
53.3
20.0
26.7
9.5 (4.1-21.7)
7.9 (2.6-24.4)
6.1 (5.4-7.0)
1.0
0.85 (0.22-3.31)
0.65 (0.27-1.57)
6
9
40.0
60.0
12.4 (6.7-22.9)
4.8 (3.6-6.5)
1.0
0.39 (0.20-0.79)
Table 2 TB Factors associated with tuberculosis in the first year after HAART onset
Sites with Chest X Rays TB
Sites with partial TB
screening and full
diagnostic capacities
diagnostic capacities
(9 sites; n=9903)
(6 sites; n=9510)
Baseline CD4 cells count
<25 cells/μL
25–49 cells/μL
50–99 cells/μL
100–199 cells/μL
200–350 cells/μL
>350 cells/μL
TB prophylaxis after HAART onset
No
Yes
TB programme as important entry
No
Yes
National TB incidence
Per 1% increase
1
IRR (95% CI) 1
P
IRR (95% CI) 1
P
1 (reference)
0.88 (0.68-1.14)
0.74 (0.59-0.94)
0.63 (0.51-0.78)
0.51 (0.39-0.68)
0.43 (0.29-0.64)
<.001
1 (reference)
1.29 (0.89-1.88)
1.01 (0.72-1.43)
0.95 (0.69-1.30)
0.92 (0.64-1.32)
0.83 (0.44-1.55)
n.s.
1 (reference)
0.49 (0.38-0.61)
<.001
1 (reference)
0.51 (0.01-3.72)
.508
1 (reference)
3.63 (1.45-9.08)
.006
1 (reference)
2.0 (0.83-4.86)
.125
7.33 (2.26-23.75)
.001
0.57 (0.12-2.73)
.483
Adjusted for age, sex and first-line antiretroviral regimen
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