J Neurol (2011) 258:313

DOI 10.1007/s00415-010-5744-8

REVIEW

Tuberculous meningitis in patients infected with human

immunodeficiency virus
Ravindra Kumar Garg Manish Kumar Sinha

Received: 21 June 2010 / Accepted: 1 September 2010 / Published online: 17 September 2010
Springer-Verlag 2010

Abstract Tuberculosis is the most common opportunistic

infection in human immunodeficiency virus (HIV) infected
persons. HIV-infected patients have a high incidence of
tuberculous meningitis as well. The exact incidence and
prevalence of tuberculous meningitis in HIV-infected
patients are not known. HIV infection does not significantly alter the clinical manifestations, laboratory, radiographic findings, or the response to therapy. Still, some
differences have been noted. For example, the histopathological examination of exudates in HIV-infected
patients shows fewer lymphocytes, epithelioid cells, and
Langhans type of giant cells. Larger numbers of acid-fast
bacilli may be seen in the cerebral parenchyma and
meninges. The chest radiograph is abnormal in up to 46%
of patients with tuberculous meningitis. Tuberculous
meningitis is likely to present with cerebral infarcts and
mass lesions. Cryptococcal meningitis is important in differential diagnosis. The recommended duration of treatment in HIV-infected patients is 912 months. The benefit
of adjunctive corticosteroids is uncertain. Antiretroviral
therapy and antituberculosis treatment should be initiated
at the same time, regardless of CD4 cell counts. Tuberculous meningitis may be a manifestation of paradoxical
tuberculosis-associated immune reconstitution inflammatory syndrome. Some studies have demonstrated a significant impact of HIV co-infection on mortality from
tuberculous meningitis. HIV-infected patients with multidrug-resistant tuberculous meningitis have significantly
higher mortality. The best way to prevent HIV-associated
tuberculous meningitis is to diagnose and isolate infectious
R. K. Garg (&)
M. K. Sinha
Department of Neurology, Chhatrapati Shahuji Maharaj Medical
University, Lucknow 226003, Uttar Pradesh, India
e-mail: garg50@yahoo.com

cases of tuberculosis promptly and administer appropriate

treatment.
Keywords BCG vaccination
Extrapulmonary
tuberculosis
Human immunodeficiency virus

Dexamethasone
Mycobacterium tuberculosis

Introduction
In endemic regions of tuberculosis, tuberculous meningitis
is a frequently encountered neurological disorder. Despite
adequate chemotherapy, tuberculous meningitis is fatal in
up to 50% of the cases. A high frequency of disabling
morbidity is observed among survivors [1]. Even in
advanced countries, such as the United States, tuberculous
meningitis is associated with a high mortality. It was
observed that even after a long follow-up of several years,
only 40% (total 135 patients) of confirmed cases of
tuberculous meningitis were still alive as compared to 85%
(total 75 patients) of patients with unconfirmed tuberculous
meningitis [2].
Human immunodeficiency virus (HIV)-infected patients
have a high incidence of all forms of tuberculosis,
including tuberculous meningitis. HIV infection influences
the pathological, clinical, and laboratory findings in
patients with tuberculous meningitis in various ways and
may be associated with poorer outcome. HIV tuberculosis
co-infection contributes to HIV-related pathogenesis and
often increases the viral load in HIV-infected people. In
this review, we will be discussing the impact of HIV
infection on epidemiology, pathogenesis, clinical features,
neuroimaging, and management of tuberculous meningitis.
An extensive review of the literature was performed using
the PubMed and Google Scholar databases. The search

123

terms used included HIV and tuberculosis; HIV and

tuberculous meningitis; AIDS and tuberculosis; AIDS and
tuberculous meningitis; tuberculous meningitis; meningeal
tuberculosis; and central nervous system tuberculosis.

Epidemiology
Tuberculosis is a leading cause of death among people
infected with HIV. According to the latest World Health
Organization estimate, in 2008 there were 33.4 million
HIV-infected cases [3]. In the same year, there were
approximately 1.4 million new cases of tuberculosis among
persons with HIV infection, and tuberculosis accounted for
23% of AIDS-related deaths. Worldwide, 14 million people
are currently co-infected with tuberculosis and HIV. In
some countries with high HIV prevalence, up to 80% of the
people with tuberculosis test positive for HIV [4, 5]. In
advanced stages of HIV infection, tuberculosis may have
atypical presentations, including extrapulmonary tuberculosis. Up to 25% of tuberculosis cases in HIV-infected
persons may present with extrapulmonary tuberculosis.
Extrapulmonary tuberculosis is more common with lower
CD4 cell counts [6].
Data from developed countries indicate an increasing
trend for extrapulmonary tuberculosis (including tuberculous meningitis) in the population because of prevalent
HIV infection [7, 8]. According to the latest tuberculosis
report from the United States of America, among 253,299
cases (from 1993 to 2006) 73.6% had pulmonary tuberculosis and 18.7% had extrapulmonary tuberculosis.
Approximately 5% of the cases had tuberculous meningitis.
The risk factors for extrapulmonary tuberculosis were
female sex and foreign birth of the patient, positive HIV
status, homelessness and excessive consumption of alcohol
[7]. The national tuberculosis surveillance data from 1999
to 2006 for England and Wales (a total of 55,607 cases)
also suggested an increasing trend in the proportion of
extrapulmonary tuberculosis. Among all the cases of
tuberculosis, the proportion with extrapulmonary disease
increased from 48% in 1999 to 53% in 2006. The largest
increase was seen in miliary tuberculosis, where the proportion rose threefold. The proportion of tuberculous
meningitis cases also significantly increased from 1.5%
(86) to 2% (165). Miliary tuberculosis and tuberculous
meningitis were associated with age over 60 years, foreign
birth of Indian, Pakistani, or Bangladeshi ethnic origin and
co-infection with HIV [8].
The epidemiological data of tuberculous meningitis
from resource poor countries with a very high incidence of
pulmonary tuberculosis are not readily available. In one of
the studies from a large teaching hospital in India, 375
patients (all patients admitted between 2001 and 2003)

123

J Neurol (2011) 258:313

with HIV infection were evaluated for opportunistic disease. Tuberculosis was the most common opportunistic
disease, seen in 163 patients, and 25 (7%) patients had
tuberculous meningitis [9]. In Thailand, among 114 consecutive patients with chronic meningitis, the most common causative agents were Cryptococcus neoformans
(54%) and Mycobacterium tuberculosis (37%). Out of the
43 patients with tuberculous meningitis, 3 patients were
HIV-positive [10].

Microbiology
Tuberculous meningitis is caused by Mycobacterium
tuberculosis, which is an acid-fast bacterium. An extensive
heterogeneity in the genetic composition of M. tuberculosis
has been demonstrated.
There are several strains of M. tuberculosis, which have
a distinct geographical distribution, interactions with the
host, and may even differ in their transmission potential.
The Beijing genotype of M. tuberculosis is considered a
more virulent strain which frequently affects HIV-infected
patients [11]. The Beijing M. tuberculosis genotype is
globally present with the highest prevalence found in Asia
and the territory of the former Soviet Union. In Thailand
58% of patients with tuberculous meningitis were found to
be infected with this genotype. The proportion of tuberculous meningitis caused by the Beijing strain was found
significantly higher than previously reported figure for
pulmonary tuberculosis caused by the Beijing strain [12].
In a large cohort of Vietnamese adults with tuberculous
meningitis, authors have recently demonstrated a strong
association between the Beijing genotype, drug resistance,
and HIV infection [13].

Tuberculosis and HIV infection pathogenesis

HIV co-infection results in an increased risk of all forms of
tuberculosis. In patients harboring M. tuberculosis who do
not have HIV infection, the lifetime risk of developing
tuberculosis is between 10 and 20%. However, in persons
co-infected with M. tuberculosis and HIV, the annual risk
of developing active tuberculosis may exceed 10% [14].
The pathogenesis of tuberculosis in HIV-1 infected persons
includes both reactivation of prior infection and aggravation of existing primary infection. In advanced stages of
HIV infection, a disseminated, miliary, or extrapulmonary
form of tuberculosis is much more frequent [15].
Active tuberculosis has a major impact on the course of
HIV infection. Tuberculosis can accelerate the course of
HIV disease by enhancing viral replication. Increased HIV
replication, in turn, leads to enhanced CD4 T cell

J Neurol (2011) 258:313

destruction and higher mortality in co-infected patients.

The levels of plasma viremia are reduced after successful
treatment of the active tuberculosis [16].
Several mechanisms have been proposed to explain the
tuberculosis-HIV association. For example, HIV has been
shown to impair tumor necrosis factor-alpha (TNF-a)
mediated macrophage apoptosis. Apoptosis of macrophages, in response to M. tuberculosis infection, is a critical host defense response, and decreased apoptosis may be
responsible for increased susceptibility to M. tuberculosis
in HIV-infected persons [17, 18]. In an in vitro study, in
response to HIV and tuberculosis co-infection, a variety of
genes of human macrophages were found to be up-regulated. However, genetic changes in response to HIV
infection alone were fewer in number and significantly
lower in magnitude. Normally, these genes encode for proinflammatory chemokines and cytokines, their receptors,
signaling associated genes, type-I interferon signaling
genes and genes of the tryptophan degradation pathway
[19]. According to another proposed mechanism, the HIV
infection may produce a rapid loss of M. tuberculosisspecific T helper-1 cells in the peripheral blood [20].

Pathogenesis of tuberculous meningitis

Mycobacterium tuberculosis infection is acquired by the
inhalation of bacilli as aerosols, which reach and multiply
in alveolar macrophages. Through the hematogenous
route, the bacilli reach into the central nervous system.
M. tuberculosis breaches the bloodbrain barrier (composed of tightly apposed brain microvascular endothelial
cells). The mechanisms involved in the process of breach
of the bloodbrain barrier are poorly understood. Inside the
central nervous system the bacilli produce small granulomas in the meninges and adjacent brain parenchyma. These
tuberculomas may remain dormant for several months or
years. Tuberculous meningitis develops when a caseating
Rich focus ruptures and discharges its contents into the
subarachnoid space [21]. What triggers the rupture of Rich
foci is not exactly known. Decreased immunity of the host
may be a factor. Following rupture of a Rich focus into the
cerebrospinal spaces, the content containing mycobacteria
induces an intense immune response and, subsequently,
exudate formation.
Mycobacterium tuberculosis is capable of entering and
replicating within macrophages. The microglial cells (the
resident macrophages of the brain) are the principal targets
of M. tuberculosis. Tumor necrosis factor-alpha released
from microglial cells has been shown to play a critical role
in the containment of infection, granuloma formation,
alteration of bloodbrain barrier permeability, and cerebrospinal fluid leukocytosis [1]. Several other cytokines

present in the microglia, such as b2-integrin (CD-18),

interleukin-6, interleukin-1b, chemokine (CC motif)
ligand 2 and chemokine (CC motif) ligand-5, and chemokine (CXC motif) ligand-10, are also involved in
the hosts defense mechanisms [22]. However, in patients
with tuberculous meningitis, variable cerebrospinal fluid
inflammatory responses were observed. For example, a
South African study could not demonstrate any significant
difference in the cerebrospinal fluid cytokine concentrations and CD4 counts between HIV seropositive and HIV
seronegative patients of tuberculous meningitis [23]. HIVinfected patients of tuberculous meningitis had lower
cerebrospinal fluid interleukin-10 and interferon-gamma
concentrations [24].

Pathology
The hallmark pathological feature of tuberculous meningitis is the presence of thick gelatinous exudates which are
prominent in the basilar regions of the brain. The exudates
may block the cerebrospinal fluid pathways resulting in the
development of hydrocephalus. The entrapment of intracranial vessels within exudates manifests as cerebral
infarcts. The entrapment of cranial nerves manifests as
cranial nerve palsies. The basal inflammatory process may
also affect the brain parenchyma, resulting in encephalopathy. Frequently, there is formation of cerebral
tuberculoma.
HIV infection may influence the pathological features of
tuberculous meningitis in several ways. Tuberculous exudates in the HIV-infected patients are minimal, thinner, and
of a serous type. The exudates in the HIV-positive patients
contain fewer lymphocytes, epithelioid cells, and Langhans type of giant cells as compared to HIV-negative
patients. Larger numbers of acid-fast bacilli may be seen in
the cerebral parenchyma and meninges of HIV-infected
patients. Hydrocephalus is not common. Mild ventricular
dilatation may be observed secondary to cerebral atrophy
[25]. Patients with HIV-associated tuberculous meningitis
may present with lower leukocyte counts in peripheral
blood and cerebrospinal fluid and may be more likely than
HIV-uninfected patients to have concomitant active
extrapulmonary extrameningeal tuberculosis [26].

Clinical featuresimpact of HIV infection

In immunocompetent patients, headache, vomiting, meningeal signs, focal deficits, vision loss, cranial nerve palsies, and raised intracranial pressure are the characteristic
clinical features of tuberculous meningitis. The sixth cranial nerve is the most frequently affected cranial nerve.

123

Vision loss, secondary to optic nerve involvement, is a

disabling complication. The possible reasons for optic
nerve involvement include optochiasmatic arachnoiditis, a
large hydrocephalus, optic nerve granulomas, or ethambutol toxicity. Changes in cerebral vessels are characterized by inflammation, spasms, constriction, and eventually
thrombosis of cerebral vessels. Infarcts are located at
internal capsule, basal ganglion, and thalamic regions and
frequently manifest as focal neurological deficits. Tuberculous radiculomyelopathy is characterized by the subacute
paraparesis [1].
Usually, human immunodeficiency virus infection does
not significantly alter the clinical manifestations, laboratory, or neuroimaging findings in patients with tuberculous
meningitis. However, some authors have suggested that
some clinical differences exist between immunodeficiency
virus-infected and immunodeficiency virus-negative
patients [27]. Overall, HIV-positive patients with tuberculous meningitis with higher CD4 cell counts often present
in the classic form, whereas patients with low CD4 cell
counts are more likely to present atypically [28]. Manifestations of tuberculous meningitis are subtle and less
specific in patients with low CD4 cell counts. These
patients present late in the course of the disease with a
prolonged duration of illness and a severe grade of tuberculous meningitis [28].
The most common clinical manifestations observed in
HIV-infected patients with tuberculous meningitis were
fever and an abnormal mental status [29]. The classical
clinical manifestations of tuberculous meningitis such as
fever, headache, vomiting, and weight loss occurred in
equal frequency in patients with and without HIV infection
[30]. Even in a pediatric study, both HIV-infected patients
and HIV-uninfected patients with tuberculous meningitis
had almost similar clinical manifestations [31]. A Vietnamese study observed, in a comparison to patients with
HIV-negative tuberculous meningitis, that HIV-infected
patients with tuberculous meningitis were younger in age
and were more commonly male. HIV-infected patients with
tuberculous meningitis weighed less but had a higher
incidence of other types of extrapulmonary tuberculosis
[26].
Differences in several hematological and blood biochemical parameters have also been noted. Concentrations
of aspartate transaminase and alanine aminotransferase
were significantly higher in HIV-infected patients. A
greater proportion of HIV-infected patients with tuberculous meningitis had hepatitis B surface antigenemia. The
authors suggested that these differences relate partly to the
epidemiological pattern of HIV infection (young male drug
users with a high prevalence of viral hepatitis) and partly to
the effects of systemic immunodeficiency (low weight, low
hematocrit level, and high prevalence of extrapulmonary/

123

J Neurol (2011) 258:313

meningeal tuberculosis) [26]. Other studies have also

reported frequent liver function abnormalities in these
patients [2]. HIV-infected children with tuberculous meningitis may have a lower hemoglobin level (\8 gm/dL)
[32]. These patients have more frequent concurrent pulmonary infection, even in the absence of respiratory
symptoms. Lymphadenopathy and hepatosplenomegaly
were also frequent findings in HIV-infected patients with
tuberculous meningitis [33].

Diagnosis
Cerebrospinal fluid findings
Cerebrospinal fluid examination is the cornerstone of the
diagnosis of tuberculous meningitis. The gold standard
for the diagnosis is the demonstration of M. tuberculosis
bacilli in the cerebrospinal fluid. In human immunodeficiency virus-associated tuberculous meningitis, a relatively
higher 69% positivity for smear and 87.9% positivity for
bacterial culture have been demonstrated [34].
The values of routinely measured cerebrospinal fluid
parameters are almost similar in HIV-positive and negative
patients with tuberculous meningitis [26, 31, 35]. Some
studies, however, noted a lower cerebrospinal fluid leukocyte count and a lower protein level in HIV-positive
patients [25, 33]. Patients with advanced HIV disease
usually have low numbers of lymphocytes in the peripheral
blood, which may reflect in a low lymphocyte count in the
cerebrospinal fluid. Moreover, tuberculous meningitis may
stimulate increased HIV replication in the central nervous
system, resulting in the destruction of cerebrospinal fluid
lymphocytes [34]. M. tuberculosis may be isolated from
the cerebrospinal fluid in a higher proportion of HIVinfected patients than in HIV-uninfected patients, perhaps
due to greater mycobacterial dissemination within the
central nervous system [30]. In a Vietnamese study,
microbiological confirmation of tuberculous meningitis
was obtained in 45% of HIV-positive patients, in contrast
to 33% of HIV-negative patients [26]. The quantity of acidfast bacilli seen in the cerebrospinal fluid smear appeared
to be higher, with a shorter time for detection of acid fast
bacilli in HIV-associated tuberculous meningitis than in
HIV-negative tuberculous meningitis [34]. M. tuberculosis
can be isolated from significantly smaller cerebrospinal
fluid volumes from HIV-infected individuals compared to
uninfected ones [36]. Cerebrospinal fluid examination
findings may be normal in 5% of HIV-positive patients
with tuberculous meningitis. The percentages of HIVpositive tuberculous meningitis patients with normal cerebrospinal fluid parameters are as follows: glucose 15%,
protein 40% and leukocyte count 10% [37].

J Neurol (2011) 258:313

Immunological tests such as tuberculin skin testing and

interferon gamma release assays should not be relied upon,
as HIV-related immunosuppression might be associated
with false-negative results. The frequency of false-negative
and indeterminate interferon gamma release assay results
increases with advancing immunodeficiency [38]. However, recently the quantitative region of difference (RD)-1
interferon-gamma-T-cell ELISPOT assay (an immunological test), using CSF mononuclear cells, has demonstrated
an accurate rapid test in HIV-infected patients with tuberculous meningitis [39]. Lipoarabinomannan is a glycolipid
forming part of the M. tuberculosis cell wall. The lipoarabinomannan antigen-detection test in serum or cerebrospinal fluid is a rapid and relatively simple assay.
A recent South African study evaluating the cerebrospinal
fluid lipoarabinomannan antigen has reported sensitivity
and specificity of 64 and 69%, respectively, for serum and
cerebrospinal fluid [40].
The microscopic observation drug susceptibility
(MODS) assay is a low-cost liquid mycobacterial culture
technique. In HIV-infected patients, the MODS assay
detected M. tuberculosis with greater sensitivity and speed
and ruled out tuberculosis more quickly and with fewer
indeterminate culture results in comparison to that of the
LowensteinJensen culture [41].
Chest radiography
The presence of pulmonary tuberculosis in a chest radiograph often helps in diagnosing tuberculous meningitis.
The chest radiograph is abnormal in up to 46% of HIVpositive patients with tuberculous meningitis [26]. Patients
with HIV infection and pulmonary tuberculosis may present with an atypical chest radiograph. In patients with low
CD4 cell counts, a primary tuberculosis-like pattern, with
diffuse interstitial or miliary infiltrates, little or no cavitation, and intrathoracic lymphadenopathy, is more common.
Lobar infiltrates with or without hilar adenopathy or diffuse
infiltrates resembling the interstitial pattern of Pneumocystis jirovecii pneumonia may also be seen.
Neuroimaging
The dominant neuroradiologic findings in tuberculous
meningitis include basal meningeal enhancement, hydrocephalus, tuberculoma, and infarctions in the brain parenchyma. The influence of HIV infection on intracranial
imaging of tuberculous meningitis has been extensively
investigated, and the findings suggested that basal meningeal enhancement and hydrocephalus on computed
tomography of the brain were less common in HIV-infected patients [25, 31]. HIV-infected individuals were also
more likely to present with cerebral infarcts and mass

Fig. 1 Contrast enhanced computed tomography showing basal

exudates, meningeal enhancement and ventricular dilatation in a
HIV-infected patient with tuberculous meningitis

lesions [35]. Infarcts were more commonly located in the

cortex in HIV-infected patients and basal ganglia in HIVuninfected patients [25]. (Figs. 1, 2, and 3).
Differential diagnosis
In HIV-infected patients, a variety of central nervous system opportunistic infections and malignancies need to be
considered as a differential diagnosis of tuberculous meningitis. Six features (duration of illness more than 5 days,
presence of headache, cerebrospinal fluid white blood cell
count of \1,000/mm [3], clear appearance, lymphocyte
count [30% and protein content of [100 mg/dL) favor the
diagnosis of tuberculous meningitis [1].
Cryptococcal meningitis is the most important differential diagnosis. It generally occurs in patients with very
low CD4 T cell counts (\100/lL). In cryptococcal meningitis, headache is often the most dominant and sometimes
may be the sole manifestation. In cryptococcal meningitis,
meningeal signs may not be demonstrable. Neuroimaging
evaluation is often normal. The cerebrospinal fluid examination may be normal in 16% of patients [37]. The diagnosis of cryptococcal meningitis is made by identification
of fungus in cerebrospinal fluid by India ink preparation.
Other fungi that may rarely cause meningitis in patients
with HIV infection are Coccidiodes immitis and Histoplasma capsulatum. Acute aseptic meningitis may develop

123

J Neurol (2011) 258:313

headache, confusion, and focal deficits mimicking chronic

meningitis. All these conditions produce focal lesions of
the brain and can be diagnosed on the basis of characteristic neuroimaging findings.

Treatment

Fig. 2 Gadolinium enhanced cranial magnetic resonance imaging

showing a tuberculoma in the pontine region of the brain

at the time of seroconversion. The clinical manifestations

are similar to other viral meningitis, with fever, headache,
stiff neck, photophobia, and cranial nerve palsies.
Patients with toxoplasmosis can also present with diffuse meningoencephalitis. Toxoplasmosis is a common late
complication of HIV infection, usually occuring in patients
with CD4 T cell counts \200/lL. Progressive multifocal
leukoencephalopathy and primary central nervous system
lymphoma are other conditions which may present with

In patients with tuberculous meningitis, antituberculosis

treatment should be started as quickly as possible. The
basic principles, which are applicable for the treatment of
pulmonary tuberculosis, remain the same for the treatment
of tuberculous meningitis [42].
The standard antituberculosis treatment regimens are
equally efficacious in HIV-negative and HIV-positive
patients with tuberculous meningitis. Hence, in HIV-infected patients there is no need to alter the choice or duration of
anti-tuberculosis treatment [42]. The recommended duration
of treatment for tuberculous meningitis is at least
912 months. The usual treatment consists of an initial
phase of isoniazid, a rifamycin, pyrazinamide, and ethambutol for the first 2 months. This is followed by a continuation phase of isoniazid and a rifamycin for 79 months.
World Health Organization guidelines suggest that in
patients with tuberculous meningitis, ethambutol should
preferably be replaced by streptomycin [42], as ethambutol
has the potential to cause vision impairment. Tuberculosis
patients with positive HIV status and all tuberculosis
patients living in HIV-prevalent settings should receive
daily antituberculosis treatment [43]. The incidence of
relapse and failure among HIV-positive pulmonary tuberculosis patients who are treated with intermittent antituberculosis treatment may be 23 times higher than that in
patients who received a daily intensive phase [42].

Fig. 3 Cranial magnetic resonance imaging (T2-weighted, FLAIR, and diffusion weighted images) shows an infarct in the left perisylvian region

123

J Neurol (2011) 258:313

Role of corticosteroids
The exact benefit of corticosteroids in HIV-infected
patients with tuberculous meningitis is uncertain. A study
conducted on 545 Vietnamese adults (which also included
98 HIV-infected patients) found a non-significant reduction
in death and severe disability in dexamethasone-treated
HIV-infected patients with tuberculous meningitis [44].
Still, the British Infectious Diseases Society guidelines
suggest that concomitant corticosteroids should be given
[45]. Corticosteroids may also be of possible value in the
management of tuberculous meningitis secondary to
tuberculosis associated immune reconstitution inflammatory syndrome [46].

Co-administration of antituberculosis
and antiretroviral therapy
The World Health Organization treatment guidelines recommend early antiretroviral treatment for all HIV-infected
individuals with active tuberculosis irrespective of CD4
cell count [41]. The first-line anti-retroviral therapy regimen should contain two nucleoside reverse transcriptase
inhibitors plus one non-nucleoside reverse transcriptase
inhibitor [42]. Efavirenz is a preferred non-nucleoside
reverse transcriptase inhibitor for tuberculosis HIV coinfected patients [47].
Antiretroviral therapy has been reported to reduce
tuberculosis rates by up to 90% at an individual level, by
60% at a population level, and to reduce tuberculosis
recurrence rates by 50% [42, 48]. Initiation of antiretroviral
treatment in patients with HIV/tuberculosis co-infection, if
accompanied by high levels of coverage and drug compliance, reduces the number of tuberculosis cases, mortality rates, and tuberculosis transmission [49].
Four important considerations are relevant for antituberculosis treatment in HIV-infected patients: timing of
antiretroviral therapy initiation, drug interactions between
antiretroviral therapy and rifamycins, an increased frequency of paradoxical reactions, and development of drugresistant tuberculosis.

Timing of anti-retroviral therapy initiation

It is uncertain whether antiretroviral therapy should be
started with antituberculosis therapy or after a delay.
Simultaneous initiation of antituberculosis therapy and
anti-retroviral therapy may lead to unwanted drug interactions and toxicities. Some authors suggest that anti-retroviral treatment may be delayed for those with higher
CD4 counts, but should not be delayed in those with severe

immune suppression (CD4 count \100 cells/lL) [50]. The

Center for Disease Control and Prevention recommends
that for patients with a CD4 count \100 cells/lL, antiretroviral therapy should be started after more than 2 weeks
of antituberculosis treatment [51]. Delay in initiating
antiretroviral therapy is associated with serious risk of
other opportunistic infections. The recent SAPiT trial
(starting antiretroviral therapy in tuberculosis) from South
Africa found that mortality among people co-infected with
HIV and tuberculosis could be halved if antiretroviral
therapy was initiated either within 4 weeks of starting
antituberculosis treatment or within 4 weeks of completing
the intensive phase of antituberculosis therapy [52].
According to the World Health Organization recommendations, antituberculosis treatment should be started
first, followed by antiretroviral therapy as soon as possible
after starting antituberculosis treatment, preferably within
the first 8 weeks of starting tuberculosis treatment [42].

Co-trimoxazole preventive therapy

In all HIV-positive tuberculosis patients, co-trimoxazole
preventive therapy should be initiated as soon as possible
and given throughout the course of antituberculosis treatment. Co-trimoxazole therapy substantially reduces mortality in HIV-positive tuberculosis patients. The exact
mode of activity is not clear but co-trimoxazole is known to
have preventive impact on Pneumocystis jirovecii, malaria,
toxoplasmosis, and on several other bacterial infections
[42].

Drug interactions between antiretroviral therapy

and rifamycins
Concomitant use of rifampicin and antiretroviral drugs is
likely to be complicated by drug-to-drug interactions.
These drug interactions can result in subtherapeutic antiretroviral drug concentrations, loss of antiviral efficacy,
and the development of viral resistance [43].
Rifampicin, a potent enzyme inducer of the cytochrome
P450 system, may lower serum levels of many HIV protease inhibitors and some nonnucleoside reverse transcriptase inhibitors. The World Health Organization
recommends that first-line antiretroviral therapy regimens
for tuberculosis patients are those that contain efavirenz,
since interactions of efavirenz with antituberculosis drugs
are minimal [42].
Rifabutin is a rifamycin with significantly less induction
of P450 enzymes. Therefore, rifabutin has less effect on the
serum concentrations of antiretroviral agents. In individuals who need antituberculosis treatment and who require an

123

10

antiretroviral therapy containing a boosted protease inhibitor, a rifabutin-based antituberculosis treatment is recommended [42].

Immune reconstitution inflammatory syndrome

and tuberculous meningitis
The immune reconstitution inflammatory syndrome is an
important complication of antiretroviral therapy, especially in patients with tuberculosis. There are two forms
(paradoxical and unmasking) of tuberculous immune
reconstitution inflammatory syndrome. The paradoxical
type is characterized by clinical worsening of a patient on
tuberculosis treatment, and the unmasking type is
characterized by undiagnosed tuberculosis becoming
apparent after starting antiretroviral therapy [53]. Immune
reconstitution inflammatory syndrome associated with M.
tuberculosis is common in high tuberculosis-prevalent
areas, occurring in approximately 1136% cases. Risk
factors for immune reconstitution inflammatory syndrome
include a high pathogen load and very low CD4 T-cell
count (\50 cells/lL) when anti-retroviral therapy is initiated [54].
Paradoxical neurologic tuberculosis-associated immune
reconstitution inflammatory syndrome accounts for
approximately 12% of all paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome cases
[45]. Dominant manifestations, in addition to tuberculous
meningitis, were intracranial tuberculoma and tuberculous
radiculo-myelopathy [45, 55]. Neuroimaging revealed that
in patients with meningitis, meningeal enhancement and
hydrocephalus were infrequent [55].
Paradoxical tuberculous reactions should not be labeled
as a new or resistant infection. Differential diagnoses
include failure of antituberculosis treatment because of
drug resistance or suboptimal antituberculosis drug concentrations, drug reactions, and alternative opportunistic
conditions such as toxoplasma and cryptococcal
meningitis.

Drug-resistant tuberculous meningitis in HIV-positive

patients
Multidrug-resistant tuberculosis is caused by bacteria that
are resistant to at least isoniazid and rifampicin. It has been
estimated that 440,000 people had multidrug-resistant
tuberculosis worldwide in 2008 and that one-third of them
died [56]. Drug-resistant tuberculosis is a major public
health concern in European countries as well. The estimated number of multidrug-resistant tuberculosis cases in
Europe in 2008 is approximately 81,000. Eastern European

123

J Neurol (2011) 258:313

countries have the highest rates of multidrug-resistant

tuberculosis in the world. HIV-positive tuberculosis
patients are at higher risk of harboring multidrug-resistant
tuberculosis strains. Tuberculosis patients living with HIV
in Eastern European countries are at a high risk of harboring multidrug-resistant tuberculosis strains [57].
Drug-resistant tuberculous meningitis has frequently
been reported in patients with HIV infection. For example,
out of 90 HIV-infected Brazilian patients with tuberculous
meningitis, 7% had primary resistance to isoniazid and 9%
to multidrug-resistant strains [27]. Authors from South
Africa reported drug resistance to at least isoniazid and
rifampicin in 8.6% of their patients with tuberculous
meningitis. Sixty percent of them were HIV-positive. In
this study, during the period of 19992002, 350 patients
with tuberculous meningitis were identified by cerebrospinal fluid culture for M. tuberculosis [58]. In the Vietnamese study, drug resistance to one or more first-line
drugs was found in 54.3% and multi-drug resistance in
8.7% of HIV-positive tuberculous meningitis patients. All
patients with multidrug-resistant tuberculous meningitis
died, but streptomycin and/or isoniazid resistance were not
associated with mortality [34]. In Argentina, multidrugresistance was observed in 41.6% isolates from HIVinfected patients with tuberculous meningitis. In this
investigation, 42 out of 101 isolates were multidrug-resistant strains. Ten isolates had isolated resistance to single
antituberculosis drugs. Because of multidrug-resistant
strains, tuberculous meningitis was more frequent in
patients who received irregular antituberculosis treatment
[59, 60]. Patients with multidrug-resistant tuberculous
meningitis and HIV-infection have lower cure rates and
higher mortality rates than patients with drug-susceptible
tuberculous meningitis, and most patients die within
3 months [26, 61].
In addition to drug resistance, several other mechanisms may also be responsible for treatment failure in
HIV-infected patients with tuberculosis. It has been
observed that HIV-infected individuals had significantly
low peak serum rifampicin and isoniazid concentration
compared to HIV-uninfected individuals [62]. The percent of rifampicin dose excreted in the urine positively
correlated with CD4 count, indicating greater malabsorption in patients with more advanced HIV disease
[63]. The patients with advanced HIV disease (CD4 T
cell counts \100/lL) are more prone to treatment failure
and relapse with rifampicin-resistant organisms when
treated with highly intermittent (for example, once- or
twice-weekly) rifampin or rifabutin-containing regimens
[64].
Current treatment guidelines recommend that an antituberculosis treatment regimen for multidrug-resistant
tuberculosis should include at least five drugs during the

J Neurol (2011) 258:313

intensive phase. Treatment regimen should include drugs

that a patient has not received before and to which the
bacilli are susceptible. The regimen should also include an
injectable medication. Appropriate second-line drugs, those
that produce significant concentrations in the cerebrospinal
fluid (ethionamide, cycloserine, and fluoroquinolones),
should be included. In five drug regimens, one of the
antituberculosis drugs should be fluoroquinolones. The
initial phase of 6 months should be followed by a continuation phase of 1218 months [58].

Adverse drug reactions

Adverse drug reactions are more common among HIVinfected patients than among HIV-uninfected patients
being treated for tuberculosis. Risk of drug reaction
increases with declining CD4 cell counts. The antituberculosis drugs and first-line antiretroviral drugs have many
common side effects, such as skin rashes, gastrointestinal
intolerance, hepatoxicity, central nervous system symptoms, peripheral neuropathy, and blood dyscrasias [65].
Most reactions occur in the first two months of treatment.
Skin rash is the most common reaction, and fever often
precedes and accompanies a rash. Mucous membrane
involvement is common. Severe skin reactions, which may
be fatal, include exfoliative dermatitis, StevensJohnson
syndrome, and toxic epidermal necrolysis. Rifampicinassociated anaphylactic shock and thrombocytopenia have
also been reported [46].

Prognosis
There are conflicting reports available about the effect of
HIV infection on the outcome of tuberculous meningitis.
Some authors observed no significant impact of HIV
infection on the mortality due to tuberculous meningitis
[35, 66], whereas others have reported higher mortality
rates in HIV-infected tuberculous meningitis patients [25,
26]. Two Vietnamese studies reported mortality rates of 65
and 67% in HIV-infected patients with tuberculous meningitis, in contrast to approximately 28% deaths in HIVuninfected patients [26, 34]. Advanced stage of tuberculous
meningitis, low serum sodium, and decreased cerebrospinal
fluid lymphocyte percentage were associated with
increased risk of death [34]. A CD4 T-cell count less than
50 cells/lL, infection caused by multidrug-resistant strains,
altered sensorium and hemiplegia were also found to be
associated with poor prognosis [25, 61]. Asignificantly
higher number of treatment failures in the HIV-infected
group suggests that HIV infection may influence the
response to treatment [67].

11

Prevention
Bacillus Calmette-Guerin (BCG) vaccination is effective in
preventing childhood tuberculous meningitis and miliary
tuberculosis. Unfortunately, BCG vaccination in HIVuninfected children is associated with disseminated BCG
infection and deaths. The risk of disseminated BCG disease
increased several hundred times in HIV-infected infants
compared to HIV-uninfected infants. The World Health
Organization does not recommend BCG vaccination for
children with symptomatic HIV infection [68].
According to a recent systematic review, treatment of
latent tuberculosis infection reduces the risk of active
tuberculosis in HIV-positive individuals [69]. HIV-infected
patients who have been exposed to an infectious tuberculosis patient should also receive isoniazid preventive therapy regardless of the Mantoux test result. A 9-month
course of isoniazid at a daily dose of 5 mg/kg (up to
300 mg/day) reduces the risk of active tuberculosis in
infected people by up to 90%. The protective effect is
believed to be life-long in the absence of re-infection. The
World Health Organization recommends a 3Is policy
(intensified tuberculosis case finding, infection control, and
isoniazid preventive therapy) for prevention of HIV-associated tuberculosis [5]. Several tuberculosis vaccines are
entering into field trials and have shown promise for the
future [70].

Conclusion
Tuberculous meningitis is a serious life-threatening disease, especially in HIV-infected persons. Infection by
multidrug-resistant strains poses a major challenge for the
clinician, as it is an important predictor of mortality. To
fight this deadly combination, clinicians should be aware of
the pathogenesis of infection and disease, rapid diagnosis
and identification of resistant strains, optimal regimens of
antituberculosis treatment and adjunctive corticosteroids,
and the optimal time to initiate antiretroviral therapy.
Currently, the 3Is policy remains the best way to fight this
menace.

References
1. Garg RK (2010) Tuberculous meningitis. Acta Neurol Scand
122:7590
2. Shaw JE, Pasipanodya JG, Gumbo T (2010) Meningeal tuberculosis: high long-term mortality despite standard therapy.
Medicine (Baltimore) 89:189195
3. World Health Organization and UNAIDS (2008) Global summary
of the HIV/AIDS epidemic. http://www.who.int/hiv/data/2009_
global_summary.gif. Accessed 6 Apr 2010

123

12
4. World Health Organization (2010) Global tuberculosis control: a
short update to the 2009 report. http://www.who.int/tb/
publications/global_report/2009/update/en/index.html. Accessed
6 Apr 2010
5. World Health Organization (2010) Tuberculosis and HIV.
http://www.who.int/hiv/topics/tb/en/index.html. Accessed 16 July
2010
6. Harries A, Maher D, Graham S (2004) TB/HIV: a clinical manual. World Health Organization. (WHO/HTM/TB/2004.329).
http://whqlibdoc.who.int/publications/2004/9241546344.pdf.pdf.
Accessed 6 Apr 2010
7. Peto HM, Pratt RH, Harrington TA, LoBue PA, Armstrong LR
(2009) Epidemiology of extrapulmonary tuberculosis in the
United States, 19932006. Clin Infect Dis 49:13501357
8. Kruijshaar ME, Abubakar I (2009) Increase in extrapulmonary
tuberculosis in England and Wales 19992006. Thorax
64:10901095
9. Attili VS, Singh VP, Rai M, Varma DV, Sundar S (2005) Evaluation of the status of tuberculosis as part of the clinical case
definition of AIDS in India. Postgrad Med J 81:404408
10. Helbok R, Pongpakdee S, Yenjun S, Dent W, Beer R, Lackner P
et al (2006) Chronic meningitis in Thailand. Clinical characteristics, laboratory data and outcome in patients with specific reference to tuberculosis and cryptococcosis. Neuroepidemiology
26:3744
11. Parwati I, van Crevel R, van Soolingen D (2010) Possible
underlying mechanisms for successful emergence of the Mycobacterium tuberculosis Beijing genotype strains. Lancet Infect
Dis 10:103111
12. Yorsangsukkamol J, Chaiprasert A, Prammananan T, Palittapongarnpim P, Limsoontarakul S, Prayoonwiwat N (2009)
Molecular analysis of Mycobacterium tuberculosis from tuberculous meningitis patients in Thailand. Tuberculosis (Edinb)
89:304309
13. Caws M, Thwaites G, Stepniewska K, Nguyen TN, Nguyen TH,
Nguyen TP et al (2006) Beijing genotype of Mycobacterium
tuberculosis is significantly associated with human immunodeficiency virus infection and multidrug resistance in cases of
tuberculous meningitis. J Clin Microbiol 44:39343939
14. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC et al (2003) The growing burden of tuberculosis:
global trends and interactions with the HIV epidemic. Arch Intern
Med 163:10091021
15. Golden MP, Vikram HR (2005) Extrapulmonary tuberculosis: an
overview. Am Fam Physician 72:17611768
16. Day JH, Grant AD, Fielding KL, Morris L, Moloi V, Charalambous S et al (2004) Does tuberculosis increase HIV load? J
Infect Dis 190:16771684
17. Patel NR, Swan K, Li X, Tachado SD, Koziel H (2009) Impaired
M tuberculosis-mediated apoptosis in alveolar macrophages from
HIV? persons: potential role of IL-10 and BCL-3. J Leukoc Biol
86:5360
18. Patel NR, Zhu J, Tachado SD, Zhang J, Wan Z, Saukkonen J,
Koziel H (2007) HIV impairs TNF-alpha mediated macrophage
apoptotic response to Mycobacterium tuberculosis. J Immunol
179:69736980
19. Maddocks S, Scandurra GM, Nourse C, Bye C, Williams RB,
Slobedman B et al (2009) Gene expression in HIV-1/Mycobacterium tuberculosis co-infected macrophages is dominated by M.
tuberculosis. Tuberculosis (Edinb) 89:285293
20. Geldmacher C, Schuetz A, Ngwenyama N, Casazza JP, Sanga E,
Saathoff E et al (2008) Early depletion of Mycobacterium
tuberculosis-specific T helper 1 cell responses after HIV-1
infection. J Infect Dis 198:15901598
21. Rich AR, McCordock HA (1933) Pathogenesis of tubercular
meningitis. Bull John Hopkins Hosp 52:513

123

J Neurol (2011) 258:313

22. Be NA, Kim KS, Bishai WR, Jain SK (2009) Pathogenesis of
central nervous system tuberculosis. Curr Mol Med 9:9499
23. Patel VB, Bhigjee AI, Bill PL, Connolly CA (2002) Cytokine
profiles in HIV seropositive patients with tuberculous meningitis.
J Neurol Neurosurg Psychiatry 73:598599
24. Simmons CP, Thwaites GE, Quyen NT, Torok E, Hoang DM,
Chau TT et al (2006) Pretreatment intracerebral and peripheral
blood immune responses in Vietnamese adults with tuberculous
meningitis: diagnostic value and relationship to disease severity
and outcome. J Immunol 176:20072014
25. Katrak SM, Shembalkar PK, Bijwe SR, Bhandarkar LD (2000)
The clinical, radiological and pathological profile of tuberculous
meningitis in patients with and without human immunodeficiency
virus infection. J Neurol Sci 181:118126
26. Thwaites GE, Duc Bang N, Huy Dung N, Hoang Thi Q,
Do Thi T, Nguyen TC et al (2005) The influence of HIV
infection on clinical presentation, response to treatment, and
outcome in adults with tuberculous meningitis. J Infect Dis
192:21342141
27. Croda MG, Vidal JE, Hernandez AV, Dal Molin T, Gualberto
FA, Oliveira AC (2010) Tuberculous meningitis in HIV-infected
patients in Brazil: clinical and laboratory characteristics and
factors associated with mortality. Int J Infect Dis 14:e586e591
28. Jones BE, Young SMM, Antoniskis D, Davidson PT, Kramer F,
Barnes PF (1993) Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 148:12921297
29. Yechoor VK, Shandera WX, Rodriguez P, Cate TR (1996)
Tuberculous meningitis among adults with and without HIV
infection. Experience in an urban public hospital. Arch Intern
Med 156:17101716
30. Vinnard C, Macgregor RR (2009) Tuberculous meningitis in
HIV-infected individuals. Curr HIV/AIDS Rep 6:139145
31. van der Weert EM, Hartgers NM, Schaaf HS, Eley BS, Pitcher
RD, Wieselthaler NA et al (2006) Comparison of diagnostic
criteria of tuberculous meningitis in human immunodeficiency
virus-infected and uninfected children. Pediatr Infect Dis J
25:6569
32. Karande S, Gupta V, Kulkarni M, Joshi A, Rele M (2005)
Tuberculous meningitis and HIV. Indian J Pediatr 72:755760
33. Gnaore E, Sassan-Morokro M, Kassim S, Ackah A, Yesso G,
Adjorlolo G et al (1993) A comparison of clinical features in
tuberculosis associated with infection with human immunodeficiency viruses 1 and 2. Trans R Soc Trop Med Hyg 87:5759
34. Torok ME, Chau TT, Mai PP, Phong ND, Dung NT, Chuong LV
et al (2008) Clinical and microbiological features of HIV-associated tuberculous meningitis in Vietnamese adults. PLOS One
3:e1772
35. Schutte CM (2001) Clinical, cerebrospinal fluid and pathological
findings and outcomes in HIV-positive and HIV-negative patients
with tuberculous meningitis. Infection 29:213217
36. Thwaites GE, Chau TT, Farrar JJ (2004) Improving the bacteriological diagnosis of tuberculous meningitis. J Clin Microbiol
42:378379
37. Jarvis JN, Meintjes G, Williams A, Brown Y, Crede T, Harrison
TS (2010) Adult meningitis in a setting of high HIV and TB
prevalence: findings from 4,961 suspected cases. BMC Infect Dis
10:67
38. Pai M, Lewinsohn DM (2005) Interferon-gamma assays for
tuberculosis: is anergy the Achilles heel? Am J Respir Crit Care
Med 172:519521
39. Patel VB, Singh R, Connolly C, Coovadia Y, Peer AK, Parag P
et al (2010) Cerebrospinal T Cell responses aid the diagnosis of
tuberculous meningitis in a HIV and TB endemic population. Am
J Respir Crit Care Med 182:569577. doi:10.1164/rccm.
200912-1931OC

J Neurol (2011) 258:313

40. Patel VB, Bhigjee AI, Paruk HF, Singh R, Meldau R, Connolly C
et al (2009) Utility of a novel lipoarabinomannan assay for the
diagnosis of tuberculous meningitis in a resource-poor high-HIV
prevalence setting. Cerebrospinal Fluid Res 6:13
41. Reddy KP, Brady MF, Gilman RH, Coronel J, Navincopa M,
Ticona E et al (2010) Microscopic observation drug susceptibility
assay for tuberculosis screening before isoniazid preventive
therapy in HIV-infected persons. Clin Infect Dis 50:997999
42. World Health Organization (2010) Treatment of tuberculosis:
guidelines, 4th edn. (WHO/HTM/TB/2009.420) World Health
Organization. http://whqlibdoc.who.int/publications/2010/9789
241547833_eng.pdf. Accessed 6 Apr 2010
43. Khan FA, Minion J, Pai M, Royce S, Burman W, Harries AD,
Menzies D (2010) Treatment of active tuberculosis in HIVcoinfected patients: a systematic review and meta-analysis. Clin
Infect Dis 50:12881299
44. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT,
Nguyen TC et al (2004) Dexamethasone for the treatment of
tuberculous meningitis in adolescents and adults. N Engl J Med
351:17411751
45. Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes
J (2009) British Infection Society guidelines for the diagnosis and
treatment of tuberculosis of the central nervous system in adults
and children. J Infect 59:167187
46. Pepper DJ, Marais S, Maartens G, Rebe K, Morroni C, Rangaka
MX et al (2009) Neurologic manifestations of paradoxical
tuberculosis-associated immune reconstitution inflammatory
syndrome: a case series. Clin Infect Dis 48:e96e107
47. World Health Organization (2009) Rapid advice: antiretroviral
therapy for HIV infection in adults and adolescents. http://www.
searo.who.int/LinkFiles/HIV-AIDS_Rapid_Advice_Adult_ART_
Guidelines%28web%29.pdf. Accessed 28 May 2010
48. Lawn SD, Churchyard G (2009) Epidemiology of HIV-associated
tuberculosis. Curr Opin HIV AIDS 4:325333
49. Atun RA, Lebcir RM, Drobniewski F, McKee M, Coker RJ
(2007) High coverage with HAART is required to substantially
reduce the number of deaths from tuberculosis: system dynamics
simulation. Int J STD AIDS 18:267273
50. Schiffer JT, Sterling TR (2007) Timing of antiretroviral therapy
initiation in tuberculosis patients with AIDS: a decision analysis.
J Acquir Immune Defic Syndr 44:229234
51. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H
(2009) Guidelines for prevention and treatment of opportunistic
infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV
Medicine Association of the Infectious Diseases Society of
America. MMWR Recomm Rep 58(RR-4):120
52. Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Nair G,
Bamber S et al (2010) Timing of initiation of antiretroviral drugs
during tuberculosis therapy. N Engl J Med 362:697706
53. Muller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M
(2010) Immune reconstitution inflammatory syndrome in patients
starting antiretroviral therapy for HIV infection: a systematic
review and meta-analysis. Lancet Infect Dis 10:251261
54. Valin N, Pacanowski J, Denoeud L, Lacombe K, Lalande V,
Fonquernie L et al (2010) Risk factors for unmasking immune
reconstitution inflammatory syndrome presentation of tuberculosis following combination antiretroviral therapy initiation in
HIV-infected patients. AIDS 24:15191525

13
55. Marais S, Scholtz P, Pepper DJ, Meintjes G, Wilkinson RJ,
Candy S (2010) Neuroradiological features of the tuberculosisassociated immune reconstitution inflammatory syndrome. Int J
Tuberc Lung Dis 14:188196
56. World Health Organization (2010) Drug-resistant tuberculosis now
at record levels. http://www.who.int/mediacentre/news/releases/
2010/drug_resistant_tb_20100318/en/index.html. Accessed 6 April
2010
57. World Health Organization (2010) Multidrug and extensively
drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response. WHO/HTM/TB/2010.3. http://whqlibdoc.
who.int/publications/2010/9789241599191_eng.pdf. Accessed 6
Apr 2010
58. Patel VB, Padayatchi N, Bhigjee AI, Allen J, Bhagwan B,
Moodley AA et al (2004) Multidrug-resistant tuberculous meningitis in KwaZulu-Natal, South Africa. Clin Infect Dis
38:851856
59. Cecchini D, Ambrosioni J, Brezzo C, Corti M, Rybko A, Perez M
et al (2007) Tuberculous meningitis in HIV-infected patients:
drug susceptibility and clinical outcome. AIDS 21:373374
60. Cecchini D, Ambrosioni J, Brezzo C, Corti M, Rybko A, Perez M
et al (2009) Tuberculous meningitis in HIV-infected and noninfected patients: comparison of cerebrospinal fluid findings. Int J
Tuberc Lung Dis 13:269271
61. Byrd TF, Davis LE (2007) Multidrug-resistant tuberculous
meningitis. Curr Neurol Neurosci Rep 7:470475
62. Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S et al (2004)
Decreased bioavailability of rifampin and other antituberculosis
drugs in patients with advanced human immunodeficiency virus
disease. Antimicrob Agents Chemother 48:44734475
63. Gurumurthy P, Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Padmapriyadarsini C, Swaminathan S et al (2004)
Malabsorption of rifampin and isoniazid in HIV-infected patients
with and without tuberculosis. Clin Infect Dis 38:280283
64. Li J, Munsiff SS, Driver CR, Sackoff J (2005) Relapse and
acquired rifampin resistance in HIV-infected patients with
tuberculosis treated with rifampin- or rifabutin-based regimens in
New York City, 19972000. Clin Infect Dis 41:8391
65. McIlleron H, Meintjes G, Burman WJ, Maartens G (2007)
Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune reconstitution
inflammatory syndrome. J Infect Dis 196(Suppl-1):S63S75
66. Dube MP, Holtom PD, Larsen RA (1992) Tuberculous meningitis
in patients with and without human immunodeficiency virus
infection. Am J Med 93:520524
67. Karstaedt AS, Valtchanova S, Barriere R, Crewe-Brown HH
(1998) Tuberculous meningitis in South African urban adults.
QJM 91:743747
68. World Health Organization (2010) Safety of BCG vaccine in HIVinfected children. http://www.who.int/vaccine_safety/topics/bcg/
immunocompromised/Dec_2006/en/. Accessed 6 Apr 2010
69. Akolo C, Adetifa I, Shepperd S, Volmink J (2010) Treatment of
latent tuberculosis infection in HIV infected persons. Cochrane
Database Syst Rev 1:CD000171. doi:10.1002/14651858.
CD000171.pub3
70. McShane H (2009) Vaccine strategies against tuberculosis. Swiss
Med Wkly 139:156160

123