Indian J Med Res 121, April 2005, pp 550-567
550
Human immunodeficiency virus/acquired
immunodeficiency syndrome (HIV/AIDS), since the
time of its initial description more than two decades
ago, has relentlessly spread all around the globe
showing no sign of abatement. In 2004, there were
4.9 million new infections and 3.1 million deaths due
to HIV/AIDS1, largely in the sub-Saharan Africa and
South-East Asia. Unfortunately, these are the parts
of the world where tuberculosis (TB) has been
flourishing unhindered since ages, forming a deadly
synergy. Advent of the HIV/AIDS pandemic has led
to a dramatic increase in the number of TB cases
worldwide. Globally, 9 per cent of all new TB cases
(31% in Africa) in adults were attributable to HIV/
AIDS, as were 12 per cent of the 1.8 million deaths
from TB, in the year 2000 2. As a result of
HIV/AIDS, incidence rates of TB in certain countries
have gone up by >6 per cent per year2, crippling the
already overburdened health care resources.
Considering the fact that about a third of the world’s
population is infected with  Mycobacterium
tuberculosis, more than a half of which lives in
countries ravaged by HIV/AIDS, the gravity of the
situation becomes evident3-5.
TB is a leading cause of morbidity and mortality in
patients with HIV/AIDS6,7. HIV and TB are  also
intricately linked to malnutrition, unemployment,
alcoholism, drug abuse, poverty and homelessness.
The direct and indirect costs of illness due to TB and
HIV are enormous, estimated to be more than 30 per
cent of the annual household income in developing
Key words Acquired immunodeficiency syndrome (AIDS)  - directly observed treatment short-course (DOTS) - highly active
antiretroviral therapy (HAART) - HIV-TB co-infection - human immunodeficiency virus (HIV) infection - tuberculosis (TB)
HIV-TB co-infection: Epidemiology, diagnosis & management
S.K. Sharma, Alladi Mohan* & Tamilarasu Kadhiravan
Department of Medicine, All India Institute of Medical Sciences, New Delhi &  *Department of Emergency
Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, India
Accepted February 17, 2005
HIV/AIDS pandemic has caused a resurgence of TB, resulting in increased morbidity and mortality
worldwide. HIV and Mycobacterium tuberculosis have a synergistic interaction; each accentuates
progression of the other. Clinical presentation of TB in early HIV infection resembles that
observed in immunocompetent persons. In late HIV infection, however, TB is often atypical in
presentation, frequently causing extrapulmonary disease. These factors coupled with low sputum
smear-positivity, often result in a delayed diagnosis. HIV-infected patients respond well to the
standard 6-month antituberculosis treatment regimens, although mortality is high.
Antituberculosis treatment is complicated by frequent drug-interactions with highly active
antiretroviral therapy (HAART) and adverse drug reactions are more common among HIV-infected
patients. Guidelines for the management  of patients co-infected with HIV and TB are still
evolving.  Timely institution of antituberculosis treatment using the directly observed treatment,
short-course (DOTS) strategy and HAART markedly improves the outcome of HIV-infected
patients with TB.
551
countries and have a catastrophic impact on the
economy in the developing world8. Thus, co-infection
with HIV and TB (HIV-TB) is not only a medical
malady, but a social and an economic disaster and is
aptly described as the “cursed duet”.
EPIDEMIOLOGY OF HIV-TB
According to the recent estimates by the WHO
and Joint United Nations Programme on HIV/AIDS
(UNAIDS), nearly 39.4 million people were living with
HIV/AIDS, worldwide; more than a half of them in
sub-Saharan Africa and nearly about a fifth in South
and South-East Asia1. In India, the overall prevalence
of HIV infection is less than 1 per cent and India
continues to be in the category of low prevalence
countries9. However, this blurs the actual picture of
the epidemic in a vast, populous country like India.
As per estimates, about 5.1 million people were
infected with HIV in the year 2003, in India (Fig.1) 9.
Prevalence of TB in patients with HIV infection
In contrast to western countries, where
Pneumocystis jiroveci pneumonia was the
commonest AIDS-defining illness10, in developing
countries TB is the most common life-threatening
opportunistic infection (OI) in patients with HIV/AIDS
with about 25 to 65 per cent patients with HIV/AIDS
having tuberculosis of any organ3,11-14. By the end of
2000, about 11.5 million people were co-infected with
HIV and M. tuberculosis, globally; 70 per cent of
co-infected people were in sub-Saharan Africa, 20
per cent in South-East Asia and 4 per cent in Latin
America and the Caribbean (Table I)2,6. TB accounts
for about 13 per cent of all HIV-related deaths
worldwide2,6. Of the 5.1 million HIV-infected people
in India, about half of them are co-infected with
M. tuberculosis; approximately 200,000 of these co-
infected persons will develop active TB each year in
association with HIV infection15.
HIV seroprevalence in Patients with TB
In sub-Saharan Africa, HIV seroprevalence rates
among patients with TB are high, ranging from 24 to
67 per cent2. In Asia, the rate of HIV infection among
TB patients has been lower. Studies from India have
reported HIV-seropositivity rates ranging from 0.4
to 20.1 per cent16-26. In certain cities such as Chennai
and Mumbai, a higher prevalence has been observed.
There has been a steady increase in HIV
seroprevalence rates over the years17,18,20. In Pune,
the HIV seroprevalence rate was observed to have
steadily increased from 3.2 per cent in 1991 to 20.1
per cent  in 1996, among patients with pulmonary TB
(PTB)18. HIV seroprevalence rate at a tertiary care
referral hospital at New Delhi was reported to have
increased from 0.4 per cent (1994-1999) to 9.4 per
cent (2000-2002)16,20. The occurrence of localised
epidemics and/or selection bias could be the cause of
this large regional variation in reported rates of HIV-
seropositivity among patients with TB.
HIV-TB: A BIDIRECTIONAL INTERACTION
HIV infection is the strongest of all known risk
factors for the development of TB. HIV-infected
persons are at markedly increased risk for progressive
disease following primary TB infection27-29, as well
as reactivation of latent tuberculosis infection (LTBI).
HIV infection also increases the risk of subsequent
episodes of TB from exogenous reinfection 30-32
(Fig.2). The  estimated  annual risk  of  reactivation
among  those co-infected with HIV and TB is about
5 to 8 per cent with a cumulative  lifetime  risk  of  30
per cent or  more  compared  to  a cumulative  lifetime
risk of 5 to 10 per cent  in HIV-negative  adult
patients.2,33
Th1 type immune response characterised by
adequate cell-mediated immunity is the crucial host
Table I. Numbers of adults (15-49 yr) co-infected with HIV and
TB in WHO regions by end 2000
WHO Region Number of people % of global total
co-infected with
HIV and TB (thousands)
Africa 7979 70
Americas 468 4
Eastern Mediterranean 163 1
Europe 133 1
South-East Asia 2269 20
Western Pacific 427 4
Total 11440 100
Adapted from reference 6
552 INDIAN J MED RES, APRIL  2005
defence against M. tuberculosis34. HIV infection
primarily affects those components of host immune
response responsible for cell-mediated immunity. Thus
in HIV infected individuals with LTBI, the fine
balance between M. tuberculosis and the host
immunity gets tiltled in favour of the former, resulting
in reactivation35. Moreover, the infection is poorly
contained following reactivation, resulting in
widespread dissemination causing extrapulmonary
disease. This is corroborated by experimental findings
that when peripheral blood lymphocytes of patients
with HIV-TB are exposed to  M. tuberculosis  in
vitro, they produce decreased amounts of Th1 type
cytokines, as compared with HIV-negative patients
with TB36,37.
The interaction between HIV and TB in persons
co-infected with them is bidirectional and synergistic.
The course of HIV infection is accelerated
subsequent to the development of TB and the inverse
relationship between HIV viraemia and CD4+ count
gets shifted to the right38. Compared with CD4+
count-matched HIV-infected controls without TB, the
relative risk of death and development of other OIs
is higher in HIV-TB co-infected patients 39.
Accelerated HIV progression is partly attributable to
the increased systemic immune activation in patients
with HIV-TB40.
Further, increased HIV replication has been
demonstrated locally, at sites of disease affected by
TB such as affected lung and pleural fluid, in patients
with HIV-TB41,42. Moreover, the genetic diversity of
the locally replicating HIV viral population is higher
than the circulating population and the local immune
activation also favours the development of latent HIV
infection of macrophages and dendritic cells, thereby
potentially enhancing dissemination of HIV38,42,43.
Thus in HIV-infected persons with active TB, the
sites of active TB infection act as epifoci of HIV
replication and evolution independent of systemic HIV
disease activity.38 The proximate molecular
mechanisms of increased HIV replication in patients
with HIV-TB are increasingly being understood;
increased levels of proinflammatory cytokines such
as tumour necrosis factor-?  (TNF-? ) and chemokines
such as monocyte chemotactic protein 1 (MCP1)
result in transcriptional activation of HIV genes
through activation of nuclear factor-? B (NF-? B) and
mitogen-activated protein (MAP) kinase pathways38
(Fig.3).
HIV/AIDS AND DRUG-RESISTANT TB
In early 1990s, several institutional outbreaks of
multidrug-resistant (MDR) TB among HIV-infected
patients drew attention to the problem44-48. However,
HIV infection per se does not appear to be a
predisposing factor for the development of MDR-TB.
Recent studies have found that drug-resistant TB
including MDR-TB is no more common among people
infected with HIV49,50. Inspite of this, several factors
such as (i) increased susceptibility to TB, ( ii)
increased opportunity to acquire TB due to over
crowding, exposure to patients with MDR-TB due to
increased hospital visits, and (iii) malabsorption of
antituberculosis drugs resulting in suboptimal
therapeutic blood levels inspite of strict adherence to
treatment regimen, potentially increase the chances
of MDR-TB in persons with HIV/AIDS, if not
adequately addressed51. Acquired rifamycin
monoresistance has also been described in HIV-TB
patients treated with rifapentine52.
CLINICAL, RADIOGRAPHIC AND
PATHOLOGIC FINDINGS
Unlike other opportunistic infections which occur
at CD4+ counts below 200/mm3, active TB occurs
throughout the course of HIV disease 27. Clinical
presentation of TB in HIV-infected individuals
depends on the level of immunosuppression resulting
from HIV infection. In patients with relatively intact
immune function (CD4+ count > 200/mm 3),
pulmonary TB (PTB) is more frequently seen than
extrapulmonary TB (EPTB)53,54 (Table II). In these
patients, chest radiographic findings include upper lobe
infiltrates and cavitation, similar to those in HIV-
negative individuals with PTB55. Sputum smears are
often positive for acid-fast bacilli (AFB) in these
patients. As immunosuppression progresses, EPTB
becomes increasingly common (Fig. 4). In contrast
to HIV-negative patients with EPTB, the disease is
often disseminated involving two or more non-
contiguous organs concomitantly, in patients with
HIV/AIDS11.
553
Chest radiographic findings in patients with
advanced HIV disease are characterised by frequent
lower lobe involvement, air-space consolidation similar
to bacterial pneumonia and absence of cavitation55;
sputum smears are seldom positive for AFB.
Intrathoracic lymphadenopathy is often evident in
these patients, resembling primary TB, regardless of
the prior TB exposure status57. A miliary pattern of
involvement is also associated with severe
immunosuppression57. Interestingly, a considerable
proportion of patients (10 to 20%) with advanced
immunosuppression may have apparently normal-
looking chest radiographs, yet M. tuberculosis can
be demonstrated or isolated from their sputum or
bronchoalveolar lavage fluid55,58,59. However,
computed tomography (CT) demonstrates
abnormalities such as pulmonary nodules, tuberculoma
and intrathoracic lymphadenopathy in these patients55.
In developing countries, EPTB is the commonest
cause of pyrexia of unknown origin (PUO) among
HIV-infected patients60. Common forms of
extrapulmonary involvement include extrathoracic
lymph node TB, pleural effusion, meningitis and
abdominal TB (Fig. 4). In advanced HIV/AIDS,
lymph node involvement is characterised by poor
granuloma formation with abundant AFB, in a
background of neutrophils and florid necrosis27. In
contrast to HIV-negative patients in whom pleural
effusion due to TB often resolves spontaneously, it is
progressive and remains culture-positive for
M. tuberculosis for prolonged period of time in
patients with HIV/AIDS61. In addition, pleural fluid
shows abundant mesothelial cells in these patients, a
finding reflecting poor inflammatory response due to
HIV/AIDS62.
TB meningitis is accompanied by TB elsewhere
in the body in most of the patients with HIV-TB and
the cerebrospinal fluid (CSF) is often acellular; at
times, CSF may be completely normal both in cellular
and biochemical characteristics63-65. In patients with
acellular CSF, meningeal signs may not be evident
clinically63. Apart from these differences,
intracerebral mass lesions are more commonly present
in HIV-infected patients with TB meningitis 66.
Hepatosplenic focal lesions and intraabdominal
lymphadenopathy are more common in HIV-infected
patients with abdominal TB; on the other hand, ascites
and omental thickening are less common when
compared to HIV-negative patients with abdominal
TB67. In patients with advanced HIV/AIDS,
mycobacteraemia is commonly demonstrable68,69.
Cutaneous lesions appearing as small papules or
vesiculopapules are more commonly found in HIV-
infected patients with miliary TB70. These are called
tuberculosis cutis miliaris disseminata, tuberculosis
cutis acuta generalisata and acute miliary tuberculosis
of the skin.
Severe weight loss is a common presenting feature
of HIV-infected patients presenting with TB71. Many
patients with AIDS, particularly in Africa, develop
severe wasting and this has been called “slim
disease”54. Since these patients usually have chronic
diarrhoea, the condition was thus thought to be a
consequence of HIV-enteropathy.  However, at
SHARMA et al: HIV-TB CO-INFECTION
Table II. Clinical presentation of TB in HIV-infected patients
Characteristic Late HIV Early HIV
infection* infection
Pulmonary: 50:50 80:20
extrapulmonary
disease
Clinical presentation  Often resembles Often resembles
primary TB post-primary TB
Chest radiograph
Intrathoracic Common Rare
lymphadenopathy
Lower lobe Common Rare
involvement
Cavitation Rare Common
Tuberculin anergy Common Rare
Sputum smear Less common Common
positivity
Adverse drug Common Rare
reactions
Relapse after Common Rare
treatment
* CD4+ T-lymphocyte count <200/mm3
Adapted from references 6 and 54
554 INDIAN J MED RES, APRIL  2005
Fig.1. Estimated number of HIV-infected people in India (1998-2004). Data from reference 9, adapted from reference 5.
autopsy, nearly half of HIV/AIDS patients who died
with “slim disease” were found to have disseminated
TB as compared with just over a quarter of those
dying without such wasting, suggesting that cryptic
disseminated/miliary TB may be an important cause
of wasting in these patients72.
DIAGNOSIS
HIV testing in patients with TB
Even though it is recommended that all patients
with active TB should be tested for HIV infection73,
compliance with this recommendation is poor even in
developed nations74,75. Selective HIV testing of TB
patients is considered unwise because physicians
often fail to identify the risk factors for HIV
transmission. Even when patients are questioned for
risk factors, it has been observed that, up to 5 per
cent of patients with TB, without any of the risk
factors, had HIV infection76. Though HIV is a major
risk factor for the development of TB, HIV testing is
not a component of the Revised National Tuberculosis
Control Programme (RNTCP) in India. The lack of
co-ordination between the voluntary counselling and
testing centres (VCTCs) and the directly observed
treatment short-course (DOTS) centres in India, is a
cause of concern and calls for increasing the
collaboration between the RNTCP and the National
AIDS Control Organization (NACO)77.
Diagnosis of TB in HIV/AIDS
Diagnosis of TB in HIV-infected patients is often
difficult due to several reasons (i) frequently negative
sputum smears, (ii) atypical radiographic findings.
(iii) higher prevalence of EPTB especially at
inaccessible sites, and (iv) resemblance to other
opportunistic pulmonary infections. However, the
diagnostic approach to suspected TB in a HIV-
infected individual is similar to that in
immunocompetent patients56, except that invasive
diagnostic procedures are more often required to
establish the diagnosis. Universal precautions need
to be followed meticulously. CT scan and magnetic
resonance imaging (MRI) have facilitated the
detection and characterisation of occult foci of EPTB.
Attempts should be directed towards arriving at a
bacteriological diagnosis, since multiple pathogens
often coexist78, and it is not possible to distinguish
from atypical mycobacterial infections based on
clinical and radiological findings alone. Peripheral
blood cultures need to be performed to detect
mycobacteraemia. Automated and semi-automated
555
Fig.2. Natural history of Mycobacterium tuberculosis infection in immunocompetent and HIV-infected individuals
LTBI, latent TB infection; PTB, pulmonary TB; EPTB, extrapulmonary TB; SS, sputum smear.
556 INDIAN J MED RES, APRIL  2005
liquid culture systems considerably reduce the delay
in obtaining culture results79. Several molecular
diagnostic techniques based on detection of  M.
tuberculosis specific DNA or ribosomal RNA
sequences by polymerase chain reaction (PCR) have
been developed in the recent past79. However, the
appropriate use of these tests in the diagnosis of active
TB, especially in patients with HIV/AIDS needs to
be defined27. Messenger RNA (mRNA) based PCR
techniques may be useful in assessing the response
to treatment80 and detection of mutations in the rpo-
B gene might be useful for rapid drug susceptibility
testing79.
TREATMENT OF HIV-TB CO-INFECTION
Availability of highly active antiretroviral therapy
(HAART) has significantly improved the outcome of
HIV/AIDS, in terms of prevention of OIs as well as
mortality81. Specifically, benefit in terms of prevention
of TB has been demonstrated in South Africa82 and
outcome of patients with HIV-TB co-infection has
improved over the years, attributable to improvements
in antiretroviral and antituberculosis treatment83. Thus
understandably, both antituberculosis treatment and
HAART are indispensable in the management of
patients with HIV-TB. However, substantial
pharmacokinetic interactions occur between the
rifamycin component of antituberculosis treatment
and antiretroviral drugs especially, protease inhibitors
(PIs) and non-nucleoside reverse transcriptase
inhibitors (NNRTIs)84. Moreover, short-course
antituberculosis regimens used in immunocompetent
patients are not so well studied in the setting of HIV
co-infection85.
The key therapeutic principles underlying the
treatment of HIV-TB are, (i) treatment of TB always
takes precedence over the treatment of HIV infection,
(ii) in patients who are already on HAART, the same
has to be continued with appropriate modifications
both in HAART and antituberculosis treatment, and
(iii) in patients who are not receiving HAART, the
need and timing of initiation of HAART have to be
decided after assessing the short-term risk of disease
progression and death, based on CD4+ count and type
of TB, on an individualised basis86-89.
There is no evidence regarding the appropriate time
for initiating HAART in patients with HIV-TB87. A
retrospective study found that in severely
immunosuppressed patients with HIV-TB, early
initiation of HAART was associated with reduced
mortality and disease progression90. British HIV
Association (BHIVA) recommends that if CD4+
counts are >200/mm3, HAART can be started after
completion of antituberculosis treatment, if indicated;
if CD4+ counts are 100-200/mm3, HAART can be
started after 2 months of TB treatment and when
CD4+ counts are <100/mm3, HAART has to be
initiated as soon as possible after starting
antituberculosis treatment87. Guidelines laid by the
WHO for use in resource-limited settings are depicted
in Fig.589.
Of all rifamycins, rifabutin induces hepatic
cytochrome CYP3A4 the least and is the preferred
rifamycin for concurrent administration with
HAART84. In such a case, ritonavir and hard-gel
formulation of saquinavir (PIs) and delaviridine
(NNRTI) should not be used; dosages of indinavir
and nelfinavir need to be increased to 1000 mg q8h
and 1250 mg q12h, respectively and that of rifabutin
has to be decreased to 150 mg/day, since PIs inhibit
the metabolism of rifabutin and increase the rate of
uveitis associated with rifabutin91. In resource-limited
settings where rifabutin is not available, ritonavir-
boosted saquinavir (SQV/r) is the recommended PI
and efavirenz at increased dosage (800 mg/day) is
the preferred NNRTI to be given along with two
nucleoside reverse transcriptase inhibitors, for
concurrent administration with rifampicin containing
antituberculosis regimens88.
Principles of antituberculosis treatment in the
setting of HIV-TB are identical to those for HIV-
negative adults with two exceptions85,87. In HIV-
infected patients with TB caused by or presumed to
be caused by susceptible strains of M. tuberculosis,
DOTS should be initiated with isoniazid, rifampicin/
rifabutin, pyrazinamide and ethambutol for the first
2 months followed by rifampicin and isoniazid for
the subsequent 4 months. Since rifampicin
monoresistance has been observed in HIV-infected
patients with CD4+ count less than 100/mm 3,
guidelines85 suggest that patients with advanced HIV
557
Fig.3. Effect of TB on HIV infection: At the site of active TB infection, macrophages infected with M. tuberculosis  (M
?
-Mtb) express tumour necrosis factor-?(TNF-?), which along with monocyte chemotactic protein 1(MCP 1), transcriptionally activates HIV-1 replication (1). The long terminal repeat (LTR) of HIV containstwo NF-?B sites. TNF-? induced HIV replication is mediated by increased activation of NF-?B in mononuclear cells. NF-?B, either alone or in concert with othertranscription factors, enhances the transcriptional activation of HIV-1. M
?
-Mtb may also cause further cycles of infection in CD4+ T-lymphocytes and monocytes (2).M
?
-Mtb also transactivate HIV-1 replication in newly recruited latently infected CD4+ T-lymphocytes (3). Differentiation of monocytes into dendritic cells may facilitatetransmission of HIV-1 to the CD4+ T-lymphocytes; differentiation into M? may promote establishment of latent HIV-1 infection.  Thus, the events occurring during Mtbantigen presentation at the site of active TB infection, result in increased viral replication, plasma viraemia, viral genotypic diversity and CD4+ T-lymphocyte loss.ICAM, intercellular adhesion molecule; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; TNF-?, tumor necrosis factor-?. Source: reference 38.
558 INDIAN J MED RES, APRIL  2005
Fig.4. Relative proportion of various forms of TB in immunocompetent (a) and HIV-infected individuals (b). PTB, pulmonary TB;
EPTB, extrapulmonary TB; LNTB, lymph node TB; MTB, miliary TB; DTB, disseminated TB; TBM, meningeal TB; ABDTB,
abdominal TB; GUTB, genitourinary TB. Reproduced with permission from reference 56.
559
disease should not receive twice weekly regimens,
but should be treated with daily or three times
weekly therapy in the continuation phase. Six
months is considered to be the minimum duration
of treatment for adults with HIV-TB 85,87. If there
is evidence of a slow or suboptimal response,
prolongation of the continuation phase to 7 months
(a total duration of 9 months) should be
employed85,87.
The initial response to 6-month therapy in HIV
co-infected TB patients is good and the rate of
recurrences is also similar to that of HIV-negative
patients if rifampicin is administered for at least 6
months92,93. However, higher recurrence rates have
been observed in some studies94, and were probably
due to re-infection rather than treatment failure.
Extended post-treatment isoniazid (INH) therapy has
been shown to decrease the risk of recurrence in
patients who had symptomatic HIV disease before
the diagnosis of TB95.
Role of corticosteroids
Clear guidelines do not exist regarding
corticosteroid use in HIV-TB. Studies done in HIV-
negative patients suggest that adjuvant
corticosteroid administration is essential in patients
with adrenal failure and is beneficial in those with
meningeal and pericardial TB and those developing
immune reconstitution inflammatory syndromes
(IRIS)85,96. A randomised controlled trial (RCT)
conducted in Zimbabwe found a significant
mortality benefit with 6 wk of prednisolone therapy
in HIV-infected patients with pericardial TB 97.
Whereas, another larger RCT of prednisolone in
HIV-infected patients with pleural TB, found no
significant mortality benefit98. Moreover, it was
observed that prednisolone treated patients had
significantly higher incidence of Kaposi’s
sarcoma98. Likewise, subgroup analysis of a large
RCT of prednisolone in TB meningitis found no
beneficial effect of adjuvant steroid therapy on
death or disability among HIV-infected patients 99.
The clinician should weigh the relative merits of
corticosteroid administration against the risk of
immunosuppression and decide on their utility in
each patient, individually.
Adjunct therapies in HIV-TB
Several immunomodulatory agents have been tried
as adjunctive therapy in the treatment of HIV-infected
patients with TB. These include  M. vaccae
vaccination100, thalidomide101,102, and
pentoxyphylline103. None of these agents were found
to confer any meaningful benefit. Interestingly, a
phase-1 study of adjunctive etanercept (TNF
receptor-Fc chimera) therapy in patients with HIV-
TB, found an insignificant trend towards better
response in terms of weight gain, sputum culture
conversion, cavity closure and CD4+ recovery104.
Adverse drug reactions
HIV-infected patients are more prone to develop
adverse reactions to antituberculosis drugs and need
to be carefully monitored. The risk of adverse drug
reactions (ADRs) increases with advanced
immunosuppression and majority of the ADRs occur
in the first two months of treatment. These include
skin rash, usually caused by thiacetazone and
sometimes by rifampicin and streptomycin,
gastrointestinal disturbances and drug-induced
hepatotoxicity among others5. Thiacetazone can cause
fatal ADRs and hence is contraindicated in HIV-
infected patients53. HIV-infected patients are more
prone to develop isoniazid-induced peripheral
neuropathy and all HIV-TB patients receiving
isoniazid should be given pyridoxine supplementation
(10-25 mg/day)85,87. Rifampicin reduces the
effectiveness of oral contraceptive pills and patients
should be advised to use other forms of
contraception5.
Immune reconstitution inflammatory syndromes
Paradoxical reactions, also called immune
restoration syndromes or immune reconstitution
inflammatory syndromes (IRIS) have been reported
in 32 to 36 per cent of patients with HIV-TB, within
days to weeks after the initiation of antiretroviral
treatment105-110. At times these can be delayed,
occurring after several months. Manifestations range
from isolated instances of fever to increased or initial
appearance of lymphadenopathy, new or worsening
pulmonary infiltrates, serositis, cutaneous lesions, and
SHARMA et al: HIV-TB CO-INFECTION
560 INDIAN J MED RES, APRIL  2005
Fig.5. World Health Organization guidelines on timing of antiretroviral treatment in patients with HIV-TB. OI, opportunistic infection. Source: reference 89.
561
new or expanding central nervous system mass
lesions. Consequently, some patients may develop
acute renal failure111  or acute respiratory distress
syndrome (ARDS)112. IRIS can be brief or prolonged
with multiple recurrences.
These pose a diagnostic problem and have to be
distinguished from TB treatment failure, and other
OIs common among HIV-infected patients. Recent
evidence suggests that CD4+ T-lymphocyte
percentage and ratio of CD4+ to CD8+
T-lymphocytes, rather than CD4 + T-lymphocyte
count, were the only factors independently associated
with IRIS, suggesting that unbalanced T-cell response
may be a key factor in the pathogenesis of IRIS 113,114.
In general, antiretroviral therapy should not be
interrupted if IRIS occurs. Nonsteroidal anti-
inflammatory drugs may provide some relief, but some
patients require adjunctive corticosteroid
administration.
OUTCOME
The mortality of HIV-infected patients with TB is
comparatively higher than that of HIV-negative TB
patients65,99,115,116. The mortality depends upon the
type of disease and the degree of underlying
immunosuppression. In HIV-infected patients with TB
meningitis, mortality is about 60-70 per cent, despite
adequate treatment65,99. However, with adequate
antituberculosis therapy, occurrence of TB has been
found to have no independent effect on mortality in
hospitalised HIV-infected patients117. Other OIs
which often go undiagnosed are a common cause of
death in patients with HIV-TB, especially those dying
later during antituberculosis treatment118. In a study
from south India, the median survival in HIV-infected
patients with PTB and EPTB was found to be 45 and
40 months, respectively119. Earlier studies from
Uganda and Europe have documented a median
survival of 22 to 24 months in HIV-infected patients
with TB120,121.
PREVENTION OF HIV-TB
All newly detected HIV-infected patients should
undergo a tuberculin skin test and prophylactic
therapy should be offered to those patients with LTBI
(induration ?  5 mm). Treatment of LTBI substantially
reduces the risk of developing active TB in HIV
infected patients and has also been shown to reduce
the mortality122. The protection offered lasts for
2.5 to 3 yr123,124.
However, in practice, especially in India, for
reasons not well understood, treatment of LTBI is
not widely offered. This is partly due to apprehension
regarding inadvertent monotherapy of active TB and
therapeutic nihilism on the part of physicians regarding
the effectiveness of prophylactic treatment for fixed
duration in a country where TB is endemic. Reliably
ruling out active TB is likely to prove a bottleneck
while implementing this strategy as a part of national
programme, and operational research is urgently
required in this aspect, in India.
The additional benefits of using IFN-?  assays based
on M. tuberculosis specific peptides, early secretory
antigen 6 (ESAT6) and culture filtrate protein 10
(CFP10) to diagnose LTBI in HIV-infected patients
and lifelong prophylactic treatment with isoniazid to
prevent reinfection, need to be evaluated in future
studies.
While persons known to be HIV-infected should
never be given bacille Calmette-Guerin (BCG), which
is a live attenuated vaccine, the WHO advocates that
routine immunisation of infants should nevertheless
continue in areas with a high incidence of TB and
HIV infection125. Prior BCG vaccination offers
modest protection against all forms of TB,
independent of HIV status; however, HIV infection
nullifies the protection offered by BCG against the
development of EPTB126. This is in contrast to HIV-
negative patients in whom BCG vaccination offers
maximum protection against the development of
extrapulmonary TB such as meningitis and miliary
TB127.
Conclusions
Globally, HIV/AIDS pandemic is threatening to
destabilise the control of TB. Treatment of HIV-TB
co-infection requires strong commitment and a
focussed approach. Appropriate use of HAART to
preserve immunity and treat HIV infection, ensuring
SHARMA et al: HIV-TB CO-INFECTION
562 INDIAN J MED RES, APRIL  2005
high levels of coverage and compliance is required to
prevent TB. The DOTS strategy is useful to ensure
cure of TB in patients with HIV/AIDS. A strong co-
ordination between the national TB and the AIDS
control programmes is required for effective
management of HIV-TB patients.
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Department of Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India
e-mail: sksharma@aiims.ac.in
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