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HIV InfectionRelated Tuberculosis:

Clinical Manifestations and Treatment
Timothy R. Sterling,1 Paul A. Pham,2 and Richard E. Chaisson2
Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, and 2Division of
Infectious Diseases and Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore,

Several aspects of human immunodeficiency virus (HIV) infectionrelated tuberculosis (TB) and its treatment
differ from those of TB in HIV-uninfected persons. The risk of TB and the clinical and radiographic mani-
festations of disease are primary examples. Antiretroviral therapy has a profound effect on lowering the risk
of TB in HIV-infected persons, but it can also be associated with immune reconstitution inflammatory disease
and unmasking of previously subclinical disease. There are also differences in treatment of HIV infection
related TB because of overlapping drug toxicities and drug-drug interactions between antiretroviral therapy
and anti-TB therapy.

Tuberculosis (TB) is one of the most common com- with a high burden of both HIV infection and TB [1,
plications of human immunodeficiency virus (HIV) in- 2]. In addition, many HIV-infected patients with TB
fection and a leading cause of death. Although highly particularly patients with advanced HIV disease and low
publicized outbreaks of drug-resistant TB have oc- CD4+ T lymphocyte countshave atypical chest ra-
curred in recent years, most HIV-related TB is caused diograph findings [3, 4]. For example, HIV-infected
by drug-susceptible strains. There are a number of spe- patients with TB are less likely to have cavitary pul-
cial challenges in the management of TB in HIV-in- monary disease than are HIV-uninfected patients with
fected persons, compared with HIV-uninfected persons, TB, and up to 22% of HIV-infected persons with pul-
and these challenges are the primary emphasis of this monary TB have normal chest radiograph findings [5
review. 7].
Smear-negative pulmonary disease. Consistent
CLINICAL MANIFESTATIONS OF TB with the lower prevalence of cavitary disease, HIV-in-
fected patients with TB have acid-fast smear-negative
Pulmonary disease. Although HIV-infected persons
disease more frequently than do HIV-uninfected per-
with TB may have the classic symptoms of TB (eg,
sons [8]. Because sputum smear is the principal means
productive cough, chest pain, shortness of breath, he-
of detecting TB in much of the world, smear-negative
moptysis, fever, night sweats, and/or weight loss), many
patients often do not receive a diagnosis and are often
such patients have few symptoms or have symptoms
not treated promptly, if at all. The mortality rate is
that are even less specific than those mentioned. It has
higher among such patients than among HIV-infected
been noted recently that a small proportion of HIV-
patients with smear-positive TB (because of delays in
infected patients with TB are minimally symptomatic
TB diagnosis in the former) and higher than among
or asymptomatic, particularly in developing countries
HIV-uninfected persons with smear-negative disease
(because of HIV infection) [9].
Subclinical disease. Because of the aforementioned
Reprints or correspondence: Dr Timothy R. Sterling, A2209 Medical Center North,
1161 21st Ave South, Nashville, TN 37232 ( findings, it should not be surprising that HIV-infected
Clinical Infectious Diseases 2010; 50(S3):S223S230 patients with TB may frequently have so-called sub-
 2010 by the Infectious Diseases Society of America. All rights reserved.
clinical TB. Such disease is not recognized as TB, re-
DOI: 10.1086/651495 sulting in delays in diagnosis and treatment. Often the

HIV InfectionRelated TB CID 2010:50 (Suppl 3) S223

manifestations of TB do not become apparent until the patient patients, the optimal duration of TB treatment is determined
has initiated antiretroviral therapy (see Effect of Highly Active by risk of relapse. Currently, treatment guidelines recommend
Antiretroviral Therapy [HAART] on TB Risk and Clinical Man- that the duration of TB therapy should be the same for both
ifestations). The natural history of subclinical TB in HIV- HIV-infected and HIV-uninfected persons [1214]. For pul-
infected persons is not well understood. Unlike individuals monary infection with drug-susceptible Mycobacterium tuber-
without HIV infection, in whom TB may be a chronic, low- culosis, a 6-month course of rifamycin-based therapy is the
grade condition, persons with HIV infection almost always ex- standard of care [12], because of comparable rates of TB relapse
perience progression of TB disease, ultimately leading to death among persons receiving 6-month regimens of rifamycin-based
in the absence of effective treatment. Thus, subclinical TB may therapy (eg, rifampin or rifabutin) [1518]. However, most of
represent the early stages of the disease that will inevitably the studies that have shown equal efficacy were relatively small
progress to overt illness. and not randomized. Only 2 randomized trials have been re-
Extrapulmonary disease. HIV-infected persons are also ported on relapse rate among HIV-infected persons with TB,
more likely than HIV-uninfected persons to have extrapul- compared with that among HIV-uninfected patients with TB,
monary TB, which may or may not occur with concomitant who receive 6 months of rifamycin-based therapy [19, 20].
pulmonary disease. Forty percent to 80% of HIV-infected per- These studies, both performed in settings with very high com-
sons with TB have extrapulmonary disease, compared with munity rates of TB, showed that a longer duration of therapy
10%20% of HIV-uninfected persons [10]. The risk of extra- was associated with a lower short-term recurrence rate. Perriens
pulmonary TB increases with lower CD4+ T lymphocyte count et al [19], working in former Zaire, found that 12 months of
[11]. The most common forms of extrapulmonary disease are standard rifampin-based therapy resulted in a significantly
lymphatic and pleural, but almost any site can be involved, lower recurrence rate at 18 months, compared with a 6-month
including the bone and/or joint (particularly the thoracic regimen. Fitzgerald et al [20] studied HIV-infected and HIV-
spine), soft tissue (eg, psoas muscle, which may be associated uninfected patients with TB in Haiti and found that recurrences
with spinal disease), central nervous system, and pericardium. were significantly reduced only among HIV-infected patients
when isoniazid was continued for 1 year after a 6-month stan-
TREATMENT OF HIV INFECTIONRELATED TB dard regimen for TB. In neither study were the investigators
In principle, the treatment of TB in individuals with HIV in- able to distinguish relapse from reinfection, and patients did
fection should be the same as that for patients with TB who not have access to antiretroviral therapy. Nonetheless, these
do not have HIV disease. Standard first-line therapy for TB trials suggest that, in high-burden areas, the likelihood of re-
with a 4-drug intensive treatment phase of 2 months, followed current TB is reduced by either longer treatment of the initial
by 4 months of treatment with a 2-drug regimen, is highly episode or secondary prophylactic (suppressive) therapy with
effective in patients with HIV infectionrelated TB (Table 1). isoniazid. In addition, several observational studies have sug-
Unlike treatment of HIV-uninfected patients, however, treat- gested that the relapse rate after such therapy may be higher
ment of HIV-infected patients with TB presents a myriad of among HIV-infected persons than among HIV-uninfected per-
clinical challenges regarding the duration of treatment, fre- sons, with rates of 2% among HIV-uninfected persons and
quency of administration, management of drug interactions, as high as 9% among HIV-infected persons [2123]. In an
and complications of therapy, such as drug toxicity and im- observational cohort study involving South African gold min-
mune reconstitution disease. Because such patients are being ers, Churchyard et al [24] found that secondary isoniazid pre-
treated for 2 diseases, the goals of therapy for both must be ventive therapy reduced the risk of recurrent TB substantially.
balanced so that optimal outcomes in terms of treatment re- The primary risk factor for TB recurrence among HIV-in-
sponse and prevention of drug resistance are achieved for both fected patients with TB appears to be low CD4+ T lymphocyte
conditions. count, with the risk highest among persons with a CD4+ T
Early reports of treatment outcomes in patients with HIV lymphocyte count !100 cells/mm3 [22, 23]. Low CD4+ T lym-
infectionrelated TB revealed that initial outcomes were gen- phocyte count appears to be a stronger risk factor than the
erally very good, but long-term outcomes were poor because factors that are associated with relapse in HIV-seronegative per-
of HIV infectionrelated mortality [10]. In recent years, because sons: cavitary pulmonary disease, positive sputum culture result
of more-effective treatment of HIV infection, long-term out- after 2 months of treatment, bilateral pulmonary disease, low
comes of TB therapy have improved, and additional problems, body weight, and white race [22, 25]. However, large-scale com-
such as recurrent TB, drug-drug interactions, and overlapping parative studies of risk factors for relapse in HIV-infected per-
drug toxicities, have emerged. sons with TB, compared with that in HIV-uninfected patients
Duration of treatment. Because initial responses to therapy with TB, are needed. A recent study from Botswana found that
are mostly excellent in both HIV-infected and HIV-uninfected low pyrazinamide concentrations were associated with poor

S224 CID 2010:50 (Suppl 3) Sterling et al

Table 1. Recommendations for the Treatment of HIV InfectionRelated Tuberculosis

Treatment Regimen Comments

Induction phase (8 weeks) INH, RIF, PZA, EMB daily or 3 times weekly Strongly consider initiation of antiretroviral
therapy, especially for advanced HIV dis-
ease; directly observed therapy recom-
mended; in high-burden settings, also
give TMP-SMX daily
Induction phase (8 weeks) with antiret- INH, RIF, PZA, EMB daily or 3 times weekly No dose adjustments needed; directly ob-
roviral agents with efavirenz-based regimen; nevirapine served therapy recommended
may also be given with RIF with caution;
substitute RBT for RIF, 3 times weekly
with ritonavir-boosted PI regimen; substi-
tute RBT for RIF, daily with nevirapine-
based regimen
Continuation phase (18 weeks) INH, RIF daily or 3 times weekly Directly observed therapy recommended
Continuation phase with antiretroviral INH, RIF daily or 3 times weekly with efavi- Directly observed therapy recommended
agents (18 weeks) renz- or nevirapine- based regimen; sub-
stitute RBT for RIF, 3 times weekly with
daily ritonavir-boosted PI regimen; substi-
tute RBT for RIF, daily with nevirapine-
based regimen

NOTE. EMB, ethambutol; INH, isoniazid; PI, protease inhibitor; PZA, pyrazinamide; RBT, rifabutin; RIF, rifampin; TMP-SMX, trimethoprim-sulfamethoxazole.

treatment outcome (defined as treatment failure or death), after in Drug Interactions between Rifamycins and Antiretroviral
adjusting for HIV infection and CD4+ T lymphocyte count [26]. Therapy.
Intermittent treatment. Intermittent TB therapy, given un- Treatment with trimethoprim-sulfamethoxazole. In 1999,
der direct observation, is a key component of TB treatment Wiktor et al [37] reported that trimethoprim-sulfamethoxazole,
regimens in the United States and elsewhere. Although TB re- given 1 month after initiation of anti-TB therapy, reduced mor-
lapse rates were low in the randomized, controlled clinical trials tality by 46% among HIV-1 and HIV-2coinfected patients
that formed the basis of such treatment recommendations [27], with TB in Cote DIvoire. Of note, the median CD4+ T lym-
intermittent therapy has been associated with higher relapse phocyte count in the study patients was 317 cells/mm3, and
rates than daily therapy in some observational studies [28, 29]. antiretroviral therapy was not available. Use of trimethoprim-
Of particular concern in HIV-infected persons is relapse of TB sulfamethoxazole appeared to reduce the risk of death by pre-
with rifamycin resistance that was not present on the original venting gastrointestinal and respiratory infections in this re-
M. tuberculosis isolate (ie, acquired rifamycin resistance) [30, source-poor setting. As a result, the WHO and the United
31]. Risk factors for acquired rifamycin resistance include ad- Nations Joint Programme on HIV/AIDS (UNAIDS) recom-
vanced HIV disease (eg, CD4+ T lymphocyte count !100 cells/ mend that all patients with HIV infectionrelated TB be treated
mm3), highly intermittent anti-TB therapy (eg, once or twice with trimethoprim-sulfamethoxazole during and after treat-
weekly), and low drug levels of both rifamycins and isoniazid ment for TB. In developed countries and in countries with
[3234]. Table 1 lists current recommended regimens for the good access to antiretroviral therapy, the level of relevance of
treatment of HIV infectionrelated TB. this recommendation is not apparent. In the United States, for
Treatment of HIV infectionrelated TB in pregnant women. example, the use of trimethoprim-sulfamethoxazole is restricted
TB should be treated in all pregnant women, including those to patients with CD4+ T lymphocyte counts !200 cells/mm3
with HIV infection. Treatment should include isoniazid, rif- for pneumocystis prophylaxis. But in settings where enteric
ampin, and ethambutol. Aminglycosides, such as streptomycin, infections, malaria, and bacterial respiratory infections are more
should not be used, because of their potential for causing con- common, adherence to the recommendation of the WHO and
genital deafness. Recommendations regarding the use of pyr- UNAIDS is warranted for patients with HIV infectionrelated
azinamide in pregnancy vary: it is not recommended in the TB.
United States because of limited safety data, but its use in Posttreatment isoniazid. HIV infection is associated with
pregnancy is recommended by the World Health Organization high rates of recurrent TB, particularly in developing countries
(WHO) and the International Union Against Tuberculosis and [38]. However, in such settings, recurrent disease is more likely
Lung Disease [13, 35, 36]. The use of rifampin during TB to be attributable to exogenous reinfection than to relapse [38,
therapy in pregnant women is essential, but management of 39]. A course of isoniazid after completion of standard anti-
drug-drug interactions is particularly challenging, as discussed TB treatment has been associated with lower rates of TB re-

HIV InfectionRelated TB CID 2010:50 (Suppl 3) S225

currence, particularly among HIV-infected persons [20, 24]. benefits of concomitant therapy are greatest among persons
Although this strategy has been proven to be effective in settings with low CD4+ T lymphocyte counts.
with a high incidence of TB and HIV infection, it is often not High pill burden for treatment of TB and HIV infection.
provided because of logistical constraints. Standard daily rifamycin-based anti-TB therapy includes 4
medications plus vitamin B6, with a daily pill burden of 110
EFFECT OF HIGHLY ACTIVE ANTIRETROVIRAL pills. Antiretroviral therapy can vary from a single pill (eg,
THERAPY (HAART) ON TB RISK AND CLINICAL efavirenz plus emtricitabine plus tenofovir) to several pills (eg,
MANIFESTATIONS a ritonavir-boosted protease inhibitor plus 2 nucleoside reverse-
The risk of TB among HIV-infected persons not receiving an- transcriptase inhibitors). Patients often receive additional med-
tiretroviral therapy is high, with rates ranging from 720 cases ications, including prophylaxis for opportunistic infections
per 100,000 population in the United States [40] to 8400 cases [55].
per 100,000 population in Brazil [41] and 9700 cases per Overlapping toxicity of treatment of TB and HIV infection.
100,000 population in South Africa [42]. On a population level, Hepatotoxicity is a common adverse effect of isoniazid, the
there has been a remarkably consistent 80% decrease in TB risk rifamycins, and pyrazinamide. It also occurs frequently with
among persons who receive HAART [4042]. However, even HIV-1 protease inhibitors and nonnucleoside reverse-transcrip-
after several years of HAART, the risk of TB remains higher tase inhibitors. Underlying HIV infection may also contribute
than that in HIV-uninfected persons, suggesting that immune to the risk, and concomitant hepatitis C virus infection further
restoration is not complete [43, 44]. This finding is also an increases the risk [56]. Other adverse effects, such as gastro-
important reminder to clinicians that HIV-infected persons re- intestinal upset and rash, are common with both types of med-
ceiving stable HAART remain at increased risk of TB, compared ications. Although stavudine and didanosine are less frequently
with HIV-uninfected persons. used for the treatment of HIV infection, they can cause pe-
Although immune reconstitution because of HAART has ripheral neuropathy, as can isoniazid.
long-term benefits with regard to risk of TB, it can also unmask Immune reconstitution inflammatory syndrome. Immune
TB not clinically recognized before HAART initiation (ie, sub- reconstitution inflammatory syndrome can occur in the context
clinical disease). Such HAART-associated TB can sometimes be of improved CD4+ T lymphocyte count and HIV-1 RNA level
associated with the immune reconstitution inflammatory syn- in persons receiving HAART. Although the clinical manifes-
drome [45, 46]. Consistent with this phenomenon, risk of TB tations of several opportunistic infections can be affected, TB
is particularly high during the first 3 months of HAART [43, is among the most common [57]. Clinical manifestations in-
44, 47]. It is unclear whether HAART is associated with an clude new or enlarging lymph nodes, worsening radiological
initial increase in risk of TB, compared with persons not re- features, new or worsening central nervous system TB, and new
ceiving antiretroviral therapy. or worsening serositis. Common clinical manifestations include
fever, cough, dyspnea, or abdominal pain (the latter due to
THE OPTIMAL TIMING OF HAART INITIATION organomegaly or serositis) [58].
IN PERSONS WITH HIV INFECTIONRELATED Although the debate continues about optimal timing of
TB HAART initiation in individuals with active TB, there are sev-
Among HIV-infected persons who receive a diagnosis of TB eral ongoing clinical trials assessing this issue [59]. The Starting
and do not receive HAART, the mortality rate is high (as high Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT)
as 91% among persons with AIDS) [10, 48, 49]. Initiation of trial reported preliminary findings that survival was improved
HAART is associated with improved survival among all HIV- among persons initiating HAART during anti-TB therapy, com-
infected persons, including those with TB [5054]. It is there- pared with waiting until after completion of anti-TB therapy
fore recommended that HIV-infected patients with TB receive [60]. A second phase of the study is comparing HAART ini-
treatment for both diseases, regardless of their CD4+ T lym- tiation within 2 months with HAART initiation 26 months
phocyte count. However, the optimal timing of HAART ini- after anti-TB therapy initiation. Several other controlled clinical
tiation in relation to the time of anti-TB therapy initiation is trials addressing this issue are also under way. A randomized
unclear. In contrast to the survival benefit provided by HAART, trial of immediate versus deferred HAART in patients with
the disadvantages of concomitant treatment of both diseases HIV-related TB meningitis in Vietnam recently reported an
include a high pill burden, multiple and overlapping drug tox- increased rate of adverse reactions among those treated early,
icities, and the possibility of paradoxical worsening of TB in with no difference in mortality or progression of HIV disease
the context of immune reconstitution. In addition, there are [61]. Use of HAART in patients with active infection of the
drug-drug interactions, particularly between rifamycins and central nervous system, such as TB or cryptococcal meningitis,
several potent antiretroviral therapy agents. Both the risks and may lead to immune reconstitution inflammatory events with

S226 CID 2010:50 (Suppl 3) Sterling et al

Table 2. Management of Interactions among Drugs Used to Treat Tuberculosis (TB) and HIV Infection

HIV infection treatment TB treatment Interaction Recommendation

PIs, unboosted (no ritonavir)
Atazanavir, indinavir, nelfinavir, and Rifampin Rifampin reduces Cmax, AUC, and Do not coadminister
saquinavir trough by 180%
Atazanavir, indinavir, and nelfinavir Rifabutin Increased concentrations of rifabutin Rifabutin and unboosted PIs may be coadminis-
with variable effects on PI tered (with dose adjustment), but alternative
exposure regimens are preferred because of limited
safety and efficacy data
PIs, boosted (with ritonavir)
Lopinavir, fosamprenavir, atazanavir, Rifampin Rifampin reduces Cmax, AUC, and Do not use
indinavir, darunavir, and tipranavir trough significantly; double dosing
of PI is toxic and may not over-
come interaction
Rifabutin Modest decreases in PI exposure; ri- Usual PI administered with ritonavir; rifabutin
tonavir increases rifabutin expo- dosage of 150 mg every other day
sure, potentially resulting in toxicity
Nonnucleoside reverse-transcriptase
Efavirenz Rifampin Rifampin reduces efavirenz exposure Administer both drugs at usual doses; some rec-
by 20% ommend increasing efavirenz dose to 800 mg
Rifabutin Efavirenz increases rifabutin clearance Rifabutin dosage should be increased to 450600
by 30%40% mg daily or 600 mg 3 times weekly
Nevirapine Rifampin Rifampin reduces nevirapine AUC by Avoid combination if possible because of higher
37%58% and Cmin by 37%68% rate of virological failure; use of full-dose nevi-
rapine (200 mg twice daily) with rifampin may
be effective
Rifabutin Minimal interactions May be coadministered safely at usual doses
Etravirine Rifampin Significant interaction of rifampin on Do not coadminister
etravirine exposure
Rifabutin Modest bidirectional interaction with May be coadministered with rifabutin dosage of
reductions in exposure to both 300 mg daily; do not coadminister with DRV/r
agents or SQV/r in regimen because of interaction be-
tween etravirine and DRV/r or SQV/r
Integrase inhibitors
Raltegravir Rifampin Rifampin reduces Cmax, AUC, and Do not coadminister; consider rifabutin with ralte-
trough levels by 60%70%; dou- gravir coadministration
bling raltegravir dosage to 800
twice daily improves Cmax and AUC
but does not affect reduction in
trough concentration
Rifabutin Rifabutin reduces raltegravir trough by Administer rifabutin (300 mg daily) with raltegra-
20%, but raltegravir AUC is not vir (400 mg twice daily)
Coreceptor inhibitors
Maraviroc Rifampin Rifampin reduces maraviroc exposure Do not coadminister, or increase maraviroc dos-
by 160% age to 600 mg twice daily
Rifabutin Modest impact of rifabutin on maravi- Administer maraviroc (300 mg twice daily) and ri-
roc exposure likely fabutin (300 mg daily)
Fusion inhibitors
Enfuvritide Rifampin and rifabutin No interactions No dose adjustments necessary
Nucleoside analogues
Zidovudine Rifampin Rifampin reduces zidovudine AUC by Clinical significance unknown
47%, but effect on intracellular con-
centrations unknown

NOTE. Additional information is available at [63]. AUC, area under the curve; Cmax, maximum plasma concentration of drug; Cmin, minimum concentration of
drug; DRV/r, darunavir booseted with ritonavir; PI, protease inhibitor; SQV/r, saquinavir boosted with ritonavir.

particularly adverse outcomes, unlike treatment in patients with developing countries were not available) found that HAART
opportunistic infection of other organ systems. A decision anal- initiation during the first 2 months of anti-TB therapy was
ysis addressing the timing of initiation of HAART for persons associated with improved outcomes, compared with HAART
with active TB and CD+ T lymphocyte counts !200 cells/mm3 initiation during months 26 of anti-TB therapy or after com-
that used data from developed countries (because data from pletion of anti-TB therapy [62].

HIV InfectionRelated TB CID 2010:50 (Suppl 3) S227

DRUG INTERACTIONS BETWEEN RIFAMYCINS antiretroviral therapy before the development of advanced im-
AND ANTIRETROVIRAL THERAPY munodeficiency, underscoring the importance of efforts to pro-
mote earlier detection and prompt initiation of care for persons
The primary drug-drug interactions of concern are those be-
with HIV infection worldwide.
tween rifamycins and HIV-1 protease inhibitors, nonnucleoside
reverse transcriptase inhibitors, integrase inhibitors, and CCR5 Acknowledgments
inhibitors. Table 2 summarizes the major interactions between
Potential conflicts of interest. T.S. has received research grants from
the rifamycins used to treat TB and antiretroviral agents. Pfizer. P.P. and R.C.: no conflicts.
HIV-1 protease inhibitors. Rifampin significantly decreases Supplement sponsorship. This article is part of a supplement entitled
HIV-1 protease inhibitor levels and, therefore, should generally Synergistic Pandemics: Confronting the Global HIV and Tuberculosis Ep-
idemics, which was sponsored by the Center for Global Health Policy, a
not be given in combination with this drug class. Drug inter- project of the Infectious Diseases Society of America and the HIV Medicine
action studies have shown that rifampin could possibly be given Association, through a grant from the Bill & Melinda Gates Foundation.
with ritonavir (standard dose, not pharmacological boosting
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