1670 • JID 2004:190 (1 November) • Dheda et al.
M A J O R A R T I C L E
Outcome of HIV-Associated Tuberculosis in the Era
of Highly Active Antiretroviral Therapy
Keertan Dheda,1Fiona C. Lampe,2Margaret A. Johnson,1and Marc C. Lipman1
London Medical School, London, United Kingdom
1Thoracic and HIV Medicine and
2Primary Care and Population Sciences, Royal Free Hospital, Royal Free and University College
with tuberculosis (TB) and human immunodeficiency virus (HIV) is unclear because of concerns about treatment-
We compared outcomes in patients starting TB treatment during the pre-HAART era (before 1996;
) with those in patients starting treatment during the HAART era (during or after 1996;n p 36
During a median of 3.6 years of follow-up, 49 patients died or had an AIDS event. Compared with
patients in the pre-HAART group, those in the HAART group had a lower risk of death (cumulative at 4 years,
43% vs. 22%;) and of death or having an AIDS event (69% vs. 43%;P p .012
first 2 months of TB treatment was exceptionally high in patients with CD4+cell counts !100 cells/mm3and
declined thereafter. HAART use during follow-up was associated with a marked reduction in event risk (adjusted
hazard ratio, 0.38 [95% confidence interval, 0.16–0.91]).
HAART substantially reduces new AIDS events and death in coinfected patients. Those with a
CD4+cell count !100 cells/mm3have a high event risk during the intensive phase of anti-TB treatment. These
data should be taken into account when deciding to delay HAART in coinfected patients with CD4+cell counts
Thebenefit of highlyactiveantiretroviraltherapy(HAART)inthetreatmentofpatientscoinfected
).n p 60
). Event risk within theP p .023
Despite adequate antituberculous therapy, many indi-
viduals coinfected with tuberculosis (TB) and HIVhave
an accelerated course of HIV disease and shortened
survival . In developed countries, such as the United
Kingdom and the United States, coinfected patients of-
ten have advanced levels of immunosuppression, with
low CD4+cell counts and high HIV RNA loads at the
time of diagnosis of TB [2, 3].
Since the advent of highly active antiretroviral ther-
apy (HAART), death from many HIV-related oppor-
tunistic infections has markedly decreased . It would
be expected that the same should applytoTB.However,
the introduction of HAART in this particular group of
Received 9 November 2003; accepted 14 May 2004; electronically published
29 September 2004.
Presented in part: Annual Meeting of the British Thoracic Society, London, 4–
6 December 2002 (abstract 158).
Reprints or correspondence: Dr. K. Dheda, Dept. of HIV and Thoracic Medicine,
Royal Free Hospital, Royal Free and University College London Medical School,
London NW3 2QG, UK (email@example.com).
The Journal of Infectious Diseases
? 2004 by the Infectious Diseases Society of America. All rights reserved.
patients is problematic because there arepotentialcom-
plex drug interactions, overlapping adverse reactions,
noncompliance due to the pill burden of multidrug
therapy, and drug malabsorbtion . There is also
increasing concern about paradoxical reactions,which
may be severe [5–7]. Therefore, it is unclear how
HAART will affect the outcome in such coinfected pa-
tients. Published data that have directly assessed the
effect of HAART on survival and new AIDS-defining
illnesses are few [8, 9], there are no data on long-term
outcome, and current antiretroviral treatment guide-
lines for coinfected patients are largely based on expert
opinion [10, 11]. Moreover, in severely immunocom-
promised patients (those with a CD4+cell count !100
cells/mm3), clinicians are faced with the dilemma of
delaying HAART to avoid treatment-related compli-
cations and paradoxical reactions or risking death or
morbidity from new AIDS-defining illnesses. This risk
assessment, which is influenced by the level of im-
munosuppression and the likelihood of opportunistic
infection, is difficult because there are no data on the
rates of death and new AIDS-defining illnesses during
the intensive and continuation phases of TB treatment
by guest on February 2, 2016
1676 • JID 2004:190 (1 November) • Dheda et al.
completion of the intensive phase of TB treatment, to reduce
both the severity of paradoxical reactions and the pill burden
. However, our data suggest that the deferment of HAART
in this subgroup is at the expense of a significant risk of death
and new AIDS-defining illnesses during this early period.
Although the start of HAART may precipitate paradoxical
reactions , it is also possible that TB itself may exert an
immunosuppressive effect that is reduced with progressive an-
timycobacterial treatment. Hence, TB treatment could contrib-
ute to immune reconstitution and a delayed inflammatory re-
sponse to TB or other occult infections . However, the
lower rates of AIDS-defining illnesses in group 2 at all stages
of TB treatment suggest that the net effect of HAART is a
reduction of the risk of OI and death in coinfected patients.
The obvious limitations of a retrospective study like ours are
bias generated by the exclusion of patients whoweretransferred
to other centers, missing data, variability in the prescribing
habits of clinic doctors, and the possibility that we may not
have identified all coinfected patients, despite our best efforts.
It is also possible that some patients may have died before HIV
testing. However, death in patientsingroup 1(15%at6months
and 20% at 12 months) was consistent with the results of
prospective studies that have reported survival data in co-
infected patients [15, 16]. The lack of prospective designed
studies in coinfected patients receiving HAART may reflect the
difficulty in obtaining sufficient numbers of case subjects to
have adequate power to identify the optimal time and CD4+
cell count at which HAART should be introduced.
To ensure that our cohort was representative of day-to-day
practice, we used a broader diagnostic definition of TB by
including patients with a clinical diagnosis of TB. Because ap-
proximately one-third of patients coinfected with TB and HIV
who complete a course of TB therapy turn out to be culture
negative , limiting analyses to culture-positive TB [8, 9]
may bias the study findings. It might be arguedthatourbroader
inclusion criteria may overdiagnose TB. However, our survival
outcomes were similar when patients with a clinical diagnosis
of TB were excluded from our analysis. The difference in de-
mographic characteristics between the 2 groups of coinfected
patients in our study reflects the increased entry of immigrants
and refugees to the United Kingdom in recent yearsfromcoun-
tries where TB is endemic.
In conclusion, our data suggest that the use of HAART in
patients coinfected with TB and HIV results in a substantial
reduction in the immediate and long-term risk of death and
the development of new AIDS-defining illnesses. Coinfected
patients with a CD4+cell count !100 cells/mm3are at partic-
ularly high risk of death or new AIDS-defining illnesses dur-
ing the early phase of TB treatment. However, it is this very
group, which is at significant risk for immune reconstitution,
that should be closely monitored for paradoxical reactions if
HAART is begun concurrently with TB treatment. Ourfindings
based on retrospective observational data require confirmation
in prospective studies.
1. Whalen C, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner
J. Accelerated course of human immunodeficiency virus infectionafter
tuberculosis. Am J Respir Crit Care Med 1995;151:129–35.
2. Kirk O, Gatell JM, Mocroft A, et al. Infections with Mycobacterium
tuberculosis and Mycobacterium avium among HIV-infected patients
after the introduction of highly active antiretroviral therapy.EuroSIDA
Study Group JD. Am J Respir Crit Care Med 2000;162:865–72.
3. Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes
PF. Relationship of the manifestations of tuberculosis to CD4 cell
counts in patients with human immunodeficiency virus infection. Am
Rev Respir Dis 1993;148:1292–7.
4. Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality
across Europe in patients infected with HIV-1. EuroSIDAStudyGroup.
5. Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the
era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001;
6. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical wors-
ening of tuberculosis following antiretroviral therapy in patients with
AIDS. Am J Respir Crit Care Med 1998;158:157–61.
7. Fishman JE, Saraf-Lavi E, Narita M, Hollender ES, Ramsinghani R,
Ashkin D. Pulmonary tuberculosis in AIDS patients: transient chest
radiographic worsening after initiation of antiretroviral therapy. AJR
Am J Roentgenol 2000;174:43–9.
8. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in
HIV-infected persons in the era of highly active antiretroviral therapy.
9. Girardi E, Palmieri F, Cingolani A, et al. Changing clinicalpresentation
and survival in HIV-associated tuberculosis after highly active anti-
retroviral therapy. J Acquir Immune Defic Syndr 2001;26:326–31.
10. American Thoracic Society, CentersforDiseaseControlandPrevention
and the Infectious Diseases Society. Treatment of tuberculosis. Am J
Respir Crit Care Med 2003;167:603–62.
11. World Health Organization (WHO) Global Tuberculosis Programme.
Treatment of tuberculosis: guidelines for national programmes[WHO/
CDS/TB/ 2003.313]. 3rd ed. Geneva: WHO, 2003.
12. American Thoracic Society, CentersforDiseaseControlandPrevention
and the Infectious Diseases Society. Diagnostic standards and classi-
fication of tuberculosis in adults and children. Am J Respir Crit Care
13. Le Moing V, Thiebaut R, Chene G, et al. Predictors of long-term
increase in CD4+cell counts in human immunodeficiency virus–in-
fected patients receiving a protease inhibitor–containing antiretroviral
regimen. J Infect Dis 2002;185:471–80.
14. Campbell IA, Dyson AJ. Lymph node tuberculosis: a comparison of
various methods of treatment. Tubercle 1977;58:171–9.
15. Murray J, Sonnenberg P, Shearer SC, Godfrey-Faussett P. Human im-
munodeficiency virus and the outcome of treatment for new and re-
current pulmonary tuberculosis in African patients. Am J Respir Crit
Care Med 1999;159:733–40.
16. Chaisson RE, Clermont HC, Holt EA, et al. Six-month supervised
intermittent tuberculosis therapy in Haitian patients with and without
HIV infection. Am J Respir Crit Care Med 1996;154:1034–8.
17. Antonucci G, Girardi E, Raviglione MC, Ippolito G. Risk factors for
tuberculosis in HIV-infected persons: a prospective cohort study. The
Gruppo Italiano di Studio Tubercolosi e AIDS (GISTA). JAMA 1995;
by guest on February 2, 2016