The

n e w e ng l a n d j o u r na l

of

m e dic i n e

edi t or i a l

When to Start Antiretroviral Therapy in HIV-Associated

Tuberculosis
M. Este Trk, M.D., Ph.D., and Jeremy J. Farrar, M.D., Ph.D.
Tuberculosis is the most common infectious
cause of death in persons infected with the human immunodeficiency virus (HIV). However,
many of the basic questions have remained unanswered, such as when to start antiretroviral
therapy (ART) in HIV-infected patients who pre
sent with tuberculosis. The early initiation of
ART, begun either simultaneously with or soon
after the start of tuberculosis therapy, may be
associated with clinical deterioration related to
the immune reconstitution inflammatory syndrome (IRIS), with toxic effects of drugs, drug
interactions, and a high pill burden (possibly
compromising adherence to therapy). Conversely,
a delay in initiating ART may result in AIDS-related
illness and death. Previous observational studies
have suggested that starting antiretroviral therapy during the course of tuberculosis therapy
will improve outcomes,1-4 and current guidelines
recommend that ART be initiated 2 to 8 weeks
after the initiation of tuberculosis therapy in all
patients who present with HIV-associated tuberculosis.5 A number of randomized, controlled
trials have sought to address the key question of
optimal timing for the initiation of ART in patients with HIV-associated tuberculosis, and the
data from three studies are reported in this issue
of the Journal.6-8
The Starting Antiretroviral Therapy at Three
Points in Tuberculosis (SAPIT) trial, reported in
2010 by Abdool Karim et al.,9 was an open-label,
randomized, controlled trial involving 642 HIVinfected South African patients with smear-positive pulmonary tuberculosis and CD4+ T-cell
counts of less than 500 per cubic millimeter.
Patients were randomly assigned to three treatment groups: the earlier integrated-therapy group
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(within 4 weeks after the start of tuberculosis

treatment), the later integrated-therapy group
(within 4 weeks after completion of the intensive phase of tuberculosis treatment), and the
sequential-therapy group (within 4 weeks after
completion of tuberculosis treatment). Previously, these investigators had reported that sequential therapy was associated with increased mortality, which is perhaps not surprising, given that
many patients had advanced HIV infection (median CD4+ T-cell count at baseline, 150 per mm3).
As a result, recruitment to the sequential-therapy group was halted.
In their current analysis, which focused on the
patients assigned to earlier or later integrated
therapy, Abdool Karim et al.6 found no significant difference in the incidence rate of AIDS or
death between the earlier-ART and the laterART groups. However, in a subgroup analysis involving 72 patients with a baseline CD4+ T-cell
count of less than 50 per cubic millimeter, there
was a nonsignificant reduction in the incidence
rate of AIDS or death but a significant increase
in the incidence of IRIS, with two deaths attributable to this syndrome. Furthermore, adverse
events requiring switches in antiretroviral drugs
were more frequent in the earlier-ART group.
The AIDS Clinical Trials Group Study A5221,
reported by Havlir et al.,7 was a multinational,
open-label, randomized trial involving 809 HIVinfected patients with suspected tuberculosis and
CD4+ T-cell counts of less than 250 per cubic
millimeter. Patients were randomly assigned to
two treatment groups: ART begun within 2 weeks
after the initiation of treatment for tuberculosis
and ART begun between 8 and 12 weeks after
the initiation of treatment for tuberculosis. The

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editorial

median CD4+ T-cell count at baseline was 77 per

cubic millimeter; 46% of the patients had confirmed tuberculosis, 83% of whom had pulmonary tuberculosis. As in the SAPIT trial, there
was no significant difference between the earlierART and later-ART groups with respect to the
rates of the combined outcomes of a new (previously undiagnosed) AIDS-defining illness or
death. Once again, among 285 patients with
screening CD4+ T-cell counts below 50 per cubic
millimeter, the rate of a new AIDS-defining illness or death was significantly reduced. This
benefit, however, was accompanied by a significant increase in IRIS events but with no deaths
related to this syndrome.
The Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA) study, reported
by Blanc et al.,8 was an open-label, randomized,
controlled trial involving 661 HIV-infected Cambodian patients with smear-positive tuberculosis
and CD4+ T-cell counts of 200 per cubic millimeter or lower. Patients were randomly assigned to
two treatment groups: ART initiated 2 weeks after
the start of tuberculosis treatment and ART initiated 8 weeks after the start of tuberculosis
treatment. More than 80% of the patients had
pulmonary tuberculosis, and the median baseline CD4+ T-cell count was 25 per cubic millimeter. In contrast to the other studies, this study
showed a significant reduction in mortality in
the earlier-ART group (in which ART was begun
within 2 weeks), which could perhaps be explained by the more advanced degree of immunosuppression in this study cohort. The CAMELIA
investigators also reported an increased frequency of IRIS in the earlier-ART group, including six fatal events.
The results of these three trials provide important evidence to guide clinicians who are
treating patients with HIV-associated tuberculosis. The CAMELIA study showed that ART initiated within 2 weeks was beneficial in reducing
mortality among all patients with tuberculosis
whose baseline CD4+ T-cell counts were 200 per
cubic millimeter or lower, whereas the other
two trials did not show a reduction in AIDS or
death, apart from that among patients with
baseline CD4+ T-cell counts below 50 per cubic
millimeter. Thus, earlier initiation of ART appears to be beneficial in patients with tuberculosis in whom immunosuppression is advanced.
However, this benefit comes at the expense of

an increase in the risks of IRIS and of adverse

events that lead to the switching of ART drugs.
In patients with higher CD4+ T-cell counts, the
benefit of early initiation of ART is less clear,
and it may be reasonable to defer initiation of
ART until the continuation phase of tuberculosis treatment in order to simplify treatment and
reduce the risk of complications.
One caveat in interpreting the results of these
trials is that the majority of the patients had
pulmonary tuberculosis, which has a reasonably
good prognosis, in the absence of drug resistance. Although IRIS may develop in patients
with pulmonary tuberculosis, it is rarely lifethreatening. In patients with more severe forms
of disease, such as tuberculous meningitis, mortality is much higher and intracranial IRIS may
prove fatal.10 Of relevance are the results of a
randomized, double-blind, placebo-controlled trial
involving 253 Vietnamese patients with tuberculous meningitis, in whom ART was given within
1 week or was deferred until 8 weeks after presentation.11 This trial showed no reduction in
mortality and an increased frequency of severe
adverse events in the group that received ART
within 1 week after presentation. Thus, the optimal time to initiate ART in patients with HIVassociated tuberculosis may depend not only on
the degree of immunosuppression but also on the
site of disease.
There are also a number of practical issues to
consider when treating patients who present with
HIV-associated tuberculosis outside of research
settings. First, diagnosing tuberculosis in this patient population is difficult, since confirmation
still often relies on microscopy to detect acid-fast
bacilli (the sensitivity of which is low), and smearnegative tuberculosis is common. Thus, antituberculosis therapy is often initiated on clinical
grounds, before the diagnosis of tuberculosis is
confirmed by means of culture (a test that is rarely performed in regions with scarce resources).
Conversely, the initiation of ART in HIV-infected
patients with undiagnosed tuberculosis may unmask the underlying mycobacterial infection.
Second, the high pill burden associated with
treatment with four antituberculosis drugs, three
antiretroviral drugs, and antimicrobial prophylaxis (e.g., with cotrimoxazole and fluconazole)
against opportunistic infections, as well as possible drug interactions and toxic effects, may
jeopardize the patients adherence to treatment.

n engl j med 365;16 nejm.org october 20, 2011

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1539

editorial

Third, treatment may be complicated further by

the need to treat multidrug-resistant or extensively drug-resistant tuberculosis, drug-resistant HIV
infection, or both, which would require even
more complex regimens that may be less well
tolerated.
Despite these caveats, the evidence, including
the study results presented in this issue of the
Journal, provides support for the earlier initiation
of ART in patients coinfected with HIV and tuberculosis who have advanced immunosuppression, apart from those who present with tuberculous meningitis.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Department of Medicine, University of Cambridge,
Addenbrookes Hospital, Cambridge, United Kingdom (M.E.T.);
and Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Ho
Chi Minh City, Vietnam (J.J.F.).
1. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tubercu-

losis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002;16:75-83.
2. Dheda K, Lampe FC, Johnson MA, Lipman MC. Outcome of
HIV-associated tuberculosis in the era of highly active antiretroviral therapy. J Infect Dis 2004;190:1670-6.

3. Manosuthi W, Chottanapand S, Thongyen S, Chaovavanich A,

Sungkanuparph S. Survival rate and risk factors of mortality

among HIV/tuberculosis-coinfected patients with and without
antiretroviral therapy. J Acquir Immune Defic Syndr 2006;43:
42-6.
4. Velasco M, Castilla V, Sanz J, et al. Effect of simultaneous
use of highly active antiretroviral therapy on survival of HIV
patients with tuberculosis. J Acquir Immune Defic Syndr 2009;
50:148-52.
5. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach 2010
revision. Geneva: World Health Organization, 2010.
6. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of
antiretroviral therapy with tuberculosis treatment. N Engl J Med
2011;365:1492-501.
7. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral
therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;
365:1482-91.
8. Blanc F-X, Sok T, Laureillard D, et al. Earlier versus later start
of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365:1471-81.
9. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of
initiation of antiretroviral drugs during tuberculosis therapy.
N Engl J Med 2010;362:697-706.
10. Marais S, Pepper DJ, Marais BJ, Trk ME. HIV-associated
tuberculous meningitis diagnostic and therapeutic challenges.
Tuberculosis (Edinb) 2010;90:367-74.
11. Trk ME, Yen NT, Chau TT, et al. Timing of initiation of
antiretroviral therapy in human immunodeficiency virus (HIV)
associated tuberculous meningitis. Clin Infect Dis 2011;52:
1374-83.
Copyright 2011 Massachusetts Medical Society.

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n engl j med 365;16 nejm.org october 20, 2011

The New England Journal of Medicine

Downloaded from nejm.org by anggiat purba on January 21, 2013. For personal use only. No other uses without permission.
Copyright 2011 Massachusetts Medical Society. All rights reserved.