AIDS Research and Therapy

Manosuthi et al. AIDS Res Ther (2016) 13:22

DOI 10.1186/s12981-016-0106-y

REVIEW Open Access

Integrated therapy for HIV

and tuberculosis
Weerawat Manosuthi1, Surasak Wiboonchutikul1 and Somnuek Sungkanuparph2*

Abstract 
Tuberculosis (TB) has been the most common opportunistic infection and cause of mortality among HIV-infected
patients, especially in resource-limited countries. Clinical manifestations of TB vary and depend on the degree of
immunodeficiency. Sputum microscopy and culture with drug-susceptibility testing are recommended as a standard
method for diagnosing active TB. TB-related mortality in HIV-infected patients is high especially during the first few
months of treatment. Integrated therapy of both HIV and TB is feasible and efficient to control the diseases and yield
better survival. Randomized clinical trials have shown that early initiation of antiretroviral therapy (ART) improves
survival of HIV-infected patients with TB. A delay in initiating ART is common among patients referred from TB to HIV
separate clinics and this delay may be associated with increased mortality risk. Integration of care for both HIV and TB
using a single facility and a single healthcare provider to deliver care for both diseases is a successful model. For TB
treatment, HIV-infected patients should receive at least the same regimens and duration of TB treatment as HIV-unin-
fected patients. Currently, a 2-month initial intensive phase of isoniazid, rifampin, pyrazinamide, and ethambutol, fol-
lowed by 4 months of continuation phase of isoniazid and rifampin is considered as the standard treatment of drug-
susceptible TB. ART should be initiated in all HIV-infected patients with TB, irrespective of CD4 cell count. The optimal
timing to initiate ART is within the first 8 weeks of starting antituberculous treatment and within the first 2 weeks for
patients who have CD4 cell counts <50 cells/mm3. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART
remains a first-line regimen for HIV-infected patients with TB in resource-limited settings. Although a standard dose of
both efavirenz and nevirapine can be used, efavirenz is preferred because of more favorable treatment outcomes. In
the settings where raltegravir is accessible, doubling the dose to 800 mg twice daily is recommended. Adverse reac-
tions to either antituberculous or antiretroviral drugs, as well as immune reconstitution inflammatory syndrome, are
common in patients receiving integrated therapy. Early recognition and appropriate management of these conse-
quences can reinforce the successful integrated therapy in HIV-infected patients with TB.
Keywords:  HIV, Tuberculosis, Treatment, Integrated therapy

Background cohort has clearly demonstrated that the risk of TB is

Tuberculosis (TB) is one of the most common opportun- associated with increasing immunodeficiency and TB
istic infections among HIV-infected patients especially occurrence significantly increases the risk of mortality
in resource-limited countries worldwide. In Africa and [2]. Optimal treatment of TB with good patient compli-
Asia, TB is also the most common cause of mortality in ance can lead to the successful treatment and reduction
HIV-infected population [1]. HIV changes the clinical of mortality [3].
presentation of TB from a slowly progressing disease to Antiretroviral therapy (ART) has proven to have a great
one with a high mortality rate. A prospective multicenter impact on survival rates among HIV-infected patients
with TB [2, 4, 5]. Simultaneous treatment of both TB
and HIV is required for HIV-infected patients present-
*Correspondence: somnuek.sun@mahidol.ac.th
2
Division of Infectious Diseases, Department of Medicine, Faculty ing with TB. In addition, patients in resource-limited set-
of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama 6 Road, tings with low CD4 cell counts, continue to present late
Bangkok 10400, Thailand to healthcare providers. New episodes of opportunistic
Full list of author information is available at the end of the article

© 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
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and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Manosuthi et al. AIDS Res Ther (2016) 13:22 Page 2 of 12

infections may develop within the first few months after in searching for acid-fast bacilli is variable from 31 to
ART and TB presents most frequently in this situation 80  % according to a previous review [22]. Studies from
[6, 7]. An integrated therapy of both HIV and TB based Africa found that patients with concurrent HIV and TB
on the current evidence of studies from both diseases infection have a higher frequency of smear-negative TB
has shown to be feasible and efficient in controlling the than those of HIV-uninfected patients [23]. Concentrat-
diseases and yields better survival in various clinical set- ing the specimen provided an additional positive yield
tings. This article focuses on the integrated therapy for of 36 % for the sputum-negative patients in a high HIV-
HIV-infected patients with active TB and details regard- prevalent area [24]. Currently, sputum microscopy and
ing diagnosis and treatment of TB, initiation of ART, culture in liquid medium with subsequent drug-suscep-
management of drug–drug interaction, overlapping tox- tibility testing are recommended as standard method for
icities of antituberculous and antiretroviral drugs, as well diagnosing active TB [25]. Nevertheless, the use of solid
as TB immune reconstitution inflammatory syndrome culture medium may be more cost-effective in resource-
are discussed. limited countries. In systematic review, the mean time to
detection with Löwenstein-Jensen cultures was 24  days,
Clinical manifestations of TB in HIV‑infected patients whereas automated mycobacterial liquid culture systems
TB among HIV-infected patients is resulted from reacti- had a mean time to detection of 15 days [26]. Drug resist-
vation of past infection or new infection of Mycobacte- ant TB substantially reduces survival in HIV-infected
rium tuberculosis [8]. Clinical manifestations are varying patients with TB [27, 28]. Early detection and optimal
from classic symptoms of prolonged fever, hemoptysis, treatment of drug resistant TB are crucial. Susceptibility
productive cough, weight loss, or night sweat to mini- testing of M. tuberculosis should be performed wherever
mal or nonspecific symptoms [9]. A previous study in this test is available.
Southeast Asia had reported that the presence of cough Beyond sputum microscopy, new molecular diagnos-
of any duration, fever of any duration, or night sweats tic tests provide a rapid diagnosis of active TB. Xpert
lasting 3 or more weeks in the preceding 4  weeks was MTB/RIF, the automated real-time nucleic acid amplifi-
93 % sensitive and 36 % specific for tuberculosis [10]. The cation assay, is endorsed for the diagnosis of pulmonary
clinical features of TB depend on the degree of immuno- TB by World Health Organization [29]. Overall pooled
deficiency. The presentation of pulmonary TB in AIDS sensitivity is 88 % and a pooled specificity is 99 % when
patients may be atypical and unusual [11]. TB patients used as an initial diagnostic test replacing smear micros-
with CD4 cell counts less than 200 cells/mm3 are likely copy. However, the pooled sensitivity of Xpert MTB/RIF
to have hilar or mediastinal adenopathy on chest radio- decreases to 79  % for HIV-infected patients [29]. Other
graphs, but less likely to have cavitary lesion [12]. Miliary molecular tests, including MTBDRplus and LightCycler
infiltrate is commonly found on chest radiographs among Mycobacterium Detection have demonstrated specifici-
AIDS patients [13]. Normal radiographs can be found in ties of more than 97  %, but the sensitivities reduced by
14–22 % of HIV-associated TB [14, 15]. 6  % when comparing with Xpert MTB/RIF test in HIV-
Extrapulmonary TB is common in HIV-infected infected patients with pulmonary TB [30]. A tubercu-
patients and can be seen in up to 60  % of HIV-infected lin skin test and an interferon-gamma release assay are
patients with TB [16, 17]. Patients with lower CD4 cell unable to distinguish latent TB from active disease [8].
counts have the higher risk of extrapulmonary TB and Usefulness of lipoarabinomannan (LAM) antigen-detec-
mycobacteremia [18]. The frequent forms of extrapul- tion assay for the diagnosis of active TB in HIV-infected
monary disease are lymphadenitis, disseminated or patients has recently been found to decrease mortality
bloodstream infection, and TB pleuritis [17–19]. TB [31–33]. The implementation of LAM testing is likely to
meningitis is the most severe form of TB. High mortality offer the greatest benefit in healthcare facilities where
rate is observed in spite of ART [20]. Other extrapulmo- diagnostic resources are scarce and patients present with
nary sites of HIV-associated TB include bone and joint, severe illness, advanced immunosuppression, and an ina-
skin and soft tissue, pericardium, liver, spleen, kidney, bility to self-expectorate sputum [33].
gastrointestinal, and genitourinary tract [21]. For extrapulmonary disease, Ziehl-Neelsen stain helps
to detect acid-fast bacilli in tissues and smears. However,
Diagnosis of TB in HIV‑infected patients the conventional smear microscopy has limited diag-
A definitive diagnosis of TB is confirmed by culturing M. nostic value with low sensitivity [34, 35]. A recent meta-
tuberculosis organisms from a specimen obtained from analysis reported that Xpert MTB/RIF has an overall
the patient. For pulmonary TB, sputum-smear for Ziehl- sensitivity of 83.1 % and a pooled specificity of 98.7 % for
Neelsen staining is fast, inexpensive, and a highly specific the diagnosis of extrapulmonary TB [36]. Xpert MTB/RIF
method. However, the sensitivity of direct microscopy is a sensitive diagnostic test for TB detection in lymph
Manosuthi et al. AIDS Res Ther (2016) 13:22 Page 3 of 12

node samples (83.1 %) and for the detection of TB men- social support can also better reinforce this approach.
ingitis (80.5  %) while only 46.4  % pooled sensitivity was Integrated therapy for both HIV and TB by the same
shown in testing with pleural fluid [36]. In tissue sam- team of healthcare providers may provide better clinical
ples other than a lymph node, a pooled estimate of sen- outcomes and use limited resource more efficiently.
sitivity and specificity were 81.2 and 98.1 %, respectively
[37]. However, direct methods sometimes fail to detect Combination therapy of TB in general population
mycobacterium in the clinical specimens. Indirect meth- Streptomycin became the first effective treatment of TB
ods sometimes help with diagnosis of extrapulmonary in 1946, but the treatment was eventually a failure with
TB. In endemic TB areas, presence of granulomatous frequent emergence of streptomycin resistance. The
inflammation with or without caseation on histopathol- strategy to overcome the resistance problem with combi-
ogy is suggestive for TB [38]. Another indirect test such nation therapy of streptomycin, aminosalicylic acid, and
as adenosine deaminase (ADA) test has considerable evi- isoniazid was reported in the 1950s. However, the treat-
dence to support its use for diagnosis of pleural TB and ment period was not less than 1 year [54, 55]. After the
to a slightly lesser extent for TB meningitis [39]. discovery of rifampin and pyrazinamide, studies showed
that the duration of treatment could be shortened to only
Integrated therapy of HIV and TB: general concept 6  months by the inclusion of rifampicin and pyrazina-
Integrated therapy is crucial for HIV-infected patients mide in the regimen [56, 57]. Currently, a 2-month initial
with TB. The two diseases, HIV and TB, must be man- intensive phase with isoniazid, rifampin, and pyrazina-
aged simultaneously. TB-related mortality in HIV- mide, followed by 4 months of a continuation phase with
infected patients is high during the first few months of isoniazid and rifampin is considered as the standard
TB treatment [1]. Additionally, evidence from rand- treatment of drug-susceptible TB [58–60]. Ethambutol is
omized clinical trials and systemic review has shown that usually recommended as the fourth drug in the intensive
early initiation of ART improves survival of HIV-infected phase to prevent unrecognized resistance to one of the
patients with TB [20, 40–46]. Managing the two diseases three core drugs [61]. Recent clinical trials in shortening
more effectively during this critical period is therefore TB treatment duration to 4  months by moxifloxacin- or
essential to improve the patients’ survival and quality gatifloxacin-containing regimens demonstrated a higher
of life. The World Health Organization guidelines have relapse rate than those of standard regimen [62–64].
recommended ART initiation during this time period The multidrug initial intensive phase is to reduce the
[47–49]. However, ART initiation is often delayed due bacillary load by killing mycobacteria rapidly and to pre-
to various factors such as patient characteristics, over- vent the emergence of drug resistance. The continuation
lapping drug toxicities, fear of clinicians or patients, and phase of therapy is given to kill the slowly replicating or
policies of local HIV and TB programs. Delay in initiat- non-replicating subpopulation. Isoniazid provides bac-
ing ART is more common among patients referred from tericidal activity by initially killing about 95  % of bacilli
TB to HIV separate clinics [50]. Delays in the initiation during the first 2  days of treatment. Its bactericidal
of ART in HIV-infected patients with TB, particularly role is then replaced by rifampicin and pyrazinamide.
those with very low CD4 cell counts, are associated with Rifampicin and pyrazinamide are also responsible for the
increased mortality risk. sterilizing activity by killing persistent or non-replicating
The successful models of integration of care for both organisms [55, 65]. A combination of at least two fully
HIV and TB mainly use a single facility such as an inte- effective drugs was necessary to prevent the emergence
grated HIV/TB care center and a single health care of resistance [54].
provider delivering care for both diseases [51, 52]. The Pulmonary and extrapulmonary TB should be treated
advantages include providing faster initiation of ART with the same regimens [58]. Six months of standard
treatment for HIV-infected patients with TB, holistic therapy is generally considered adequate for most forms
evaluation of the patients, and practical management of extrapulmonary tuberculosis. However, treatment
when patients encounter adverse drug effects. In addi- duration may need to be extended for central nervous
tion, this model in resource-limited settings is also more system and skeletal tuberculosis. Although the optimal
feasible to set up, maintain, and train the healthcare pro- duration of therapy cannot be defined, the 9–12 months
viders. A systematic review has demonstrated that inte- duration is recommended for the treatment of TB men-
grated care of HIV and TB may overcome challenges ingitis because of serious risk of disability and mortality
such as losing patients to follow-up during the referral and for the treatment of TB of bone and joints because of
process between TB and HIV clinics, burdening patients the difficulties of assessing treatment response [58–60].
with increased travel costs and additional time spent in Adjunctive corticosteroids reduce the risk of death or
clinics [53]. Interventions for improving adherence and disabling residual neurological deficit in patients with
Manosuthi et al. AIDS Res Ther (2016) 13:22 Page 4 of 12

tuberculous meningitis [66], and may be beneficial in the risk of morbidity and mortality in very advanced HIV
those with tuberculous pericarditis [67]. An intensified disease with the potential occurrence of additive toxici-
regimen for TB meningitis that includes both a higher ties, drug–drug interactions, and TB-associated immune
dose of oral rifampicin and the addition of levofloxacin to reconstitution inflammatory syndrome (IRIS). The cur-
the standard regimen does not provide benefit on reduc- rent World Health Organization guidelines recommend
ing overall mortality [68]. that ART should be started as soon as possible “within
the first 8  weeks” of starting antituberculous treatment
Treatment of TB in HIV‑infected patients and within the first 2  weeks for patients who have CD4
The principles for treatment of active TB disease in cell counts less than 50 cells/mm3 [47–49]. The results
HIV-infected patients are the same as those for HIV- from randomized control trials have been published over
uninfected patients. TB treatment is the priority. The the past 5 years [40–44]. They have shown the same trend
regimens should include rifampicin and isoniazid [69, of survival benefit of concurrent ART during TB treat-
70]. The 6-month duration with standard regimen among ment. In addition, ART initiation within the first 2 weeks
HIV-infected patients showed similar cure and treat- of TB treatment is beneficial in patients with advanced
ment failure rates as in HIV-uninfected patients [71–73]. HIV disease, i.e., CD4 cell count <50 cells/mm3 [40–44],
However, a meta-analysis on treatment of active TB in although it is associated with a twofold higher frequency
HIV-infected patients suggested that longer duration of TB IRIS [45]. TB IRIS is generally manageable and sur-
of rifamycin therapy (at least 8  months) were associ- vival benefits of early ART in this group outweigh the risk
ated with a lower risk of TB relapse [74]. Intermittent of TB IRIS.
intensive-phase treatment was associated with increased In patients with CD4 cell counts higher than 50 cells/
odds of treatment failure [75]. ART was found to lower mm3, evidence is insufficient to support or refute a sur-
the risk of TB relapse [74]. Studies to assess duration of vival benefit conferred by early ART initiation [45].
rifamycin-based TB treatment and dosing schedule in Recently, a randomized control study in co-infected HIV
patients receiving ART are needed for further evaluation. and TB patients with high CD4 cell counts showed no
Currently, the World Health Organization’s guideline difference of mortality between early and deferred ART
for the treatment of TB recommends that HIV-infected on the unfavorable composite endpoint of death, tuber-
patients should, as a minimum, receive the same dura- culosis treatment failure, and recurrence [46]. There-
tion and daily dosing of TB treatment as HIV-uninfected fore, patients with less immune deficiency, i.e., CD4 cell
patients. ART should be initiated in all HIV-infected with counts higher than 50 cells/mm3, ART may be deferred
TB patients, irrespective of CD4 cell count [58]. until completion of intensive phase of TB treatment
Rifabutin induces CYP3A activity at a lesser magnitude without compromising survival. In addition, a study in
than rifampicin and it may therefore be a more appropri- HIV-associated TB meningitis showed that immediate
ate option for co-administration with many antiretroviral ART was not associated with reduced 9-month mortal-
drugs, including PIs [76]. Of noted, PIs increase the dose ity, when compared to deferred ART initiation [20]. The
of rifabutin. Thus, rifabutin dosage required adjustment adverse events were significantly more frequently found
to minimize rifabutin-associated toxicity, including neu- in both overall and during the first 2 months of treatment
tropenia, uveitis, and liver toxicity [59]. A concern with in immediate versus deferred ART arm [20]. Nonethe-
rifabutin 150  mg thrice weekly is that rifabutin under less, treatment guidelines in the resource-rich setting
exposure may result in acquired rifamycin resistance. recommends to start ART as soon as possible with close
Some experts recommend rifabutin at a dose of 150 mg monitoring and prompt management of adverse reac-
daily when co-administered with any ritonavir-boosted tions and central nervous system IRIS [69]. Thus, caution
PI [60, 61]. A recent randomized pharmacokinetic evalu- in early ART initiation is warranted in patients with TB
ation of different rifabutin doses in African HIV- infected meningitis. Table  1 summarizes all randomized control
patients with TB and on lopinavir/ritonavir-based ART trials of the timing to initiate ART during TB treatment.
has demonstrated that a daily 150  mg dose of rifabutin A rifamycin-containing antituberculous regimen is cru-
in combination with lopinavir/ritonavir safely main- cial in the treatment of drug-sensitive TB. The regimens
tained rifabutin plasma concentrations [77]. To date, the which do not contain rifampicin during the continuation
replacement of rifampicin by rifabutin for first-line treat- phase are significantly inferior to the standard 6-month
ment of TB is not supported by the current evidence [78]. regimen in newly diagnosed smear-positive pulmonary
TB [79]. Rifapentine, a long-acting rifamycin, is not rec-
ART in HIV‑infected patients with TB ommended for TB treatment in HIV-infected patients
The optimal timing to commence ART in HIV-infected receiving ART because of significant cytochrome P 450
patients with TB is relatively complex. It must balance induction. Both rifampin and rifabutin are less strong
Table 1  Randomized control trials determining time to initiate ART in HIV-infected patients with TB
Manosuthi et al. AIDS Res Ther (2016) 13:22

Study TB characteristics Median Study arms Mortality difference Country ART regimen
CD4 count

(1A) SAPIT 1 Smear +ve pulmonary TB 150 Integrated vs. sequential 5 vs. 12 deaths/100 PYs South Africa ddI, 3TC, EFV
Abdool Karim et al. NEJM 2010 [43] 56 % lower in integrated arm
(1B) SAPIT 2 Smear +ve pulmonary TB 150 4 vs. 8–12 weeks No differences of AIDS/death South Africa ddI, 3TC, EFV
Abdool Karim et al. NEJM 2011 [44] Lower in only CD4 <50
8 vs. 26 deaths/100 PYs
(2) CAMELIA Smear +ve pulmonary TB 25 2 vs. 8 weeks 15 vs. 26 % Cambodia d4T, 3TC, EFV
Blanc et al. NEJM 2011 [42] 38 % lower in 2-week arm
(3) STRIDE Confirmed or probable pulmo- 77 <2 vs. 8–12 weeks No differences of mortality Multi-national TDF/FTC, EFV
Havlir et al. nary TB Lower in only CD4 <50
NEJM 2011 [45] 15 vs. 27 %
(4) TOROK TB meningitis 41 <2 vs. 8 weeks No differences of time to death Vietnam AZT, 3TC, EFV
Torok et al. CID 2011 [49]
(5) TIME Confirmed or probable any TB 43 4 vs. 12 weeks Have a tendency in CD4 <50 Thailand TDF, 3TC, EFV
Manosuthi et al. JAIDS 2012 [46] 10 vs. 14 deaths/100 PYs
(6) TB-HAART Culture-confirmed TB 367 ≤2 weeks vs. 6 months No difference between early and South Africa, Uganda, Zambia, AZT, 3TC, EFV
Mfinanga et al. Lancet ID 2014 [48] late ART on composite endpoint Tanzania
of death, tuberculosis treatment
failure, and recurrence
Page 5 of 12
Manosuthi et al. AIDS Res Ther (2016) 13:22 Page 6 of 12

hepatic cytochrome P 450 inducers. However, these two not shown in a head-to-head comparison with efavirenz-
drugs upregulate the uridine diphosphate glucuronosyl- based ART. With regards to safety, nevirapine at full dose
transferase 1A1 enzymes [80]. Therefore, they are associ- could be a safe, acceptable alternative for patients unable
ated with significant drug–drug interactions in different to tolerate efavirenz and other options are not available
magnitudes with many antiretroviral drugs, including all [101]. A higher dose of nevirapine at 300 mg twice daily
protease inhibitors (PIs), non-nucleoside reverse tran- to overcome drug–drug interactions is associated with
scriptase inhibitors (NNRTIs), and integrase inhibitors. higher rates of liver toxicity [102]. Rifampicin signifi-
Despite the problem of drug–drug interactions between cantly reduces plasma concentrations of rilpivirine and
rifamycins and antiretroviral drugs, simultaneous treat- etravirine, thus, these drugs are not recommended to
ment of both TB and HIV are required. Co-administra- be co-administered with rifampicin [103]. With regards
tion of rifampin and PIs is not recommended owing to to integrase inhibitor, raltegravir co-administered with
significantly decreased plasma concentrations of all PIs rifampicin resulted in lower raltegravir minimum con-
and poor treatment outcomes [81–83]. Increasing the centration by 61  %. Doubling the dose of raltegravir to
dosage of ritonavir or other PIs has resulted in unaccep- 800 mg when co-administered with rifampicin can com-
table rates of liver toxicity and intolerability [84, 85]. A pensate the effect of rifampicin on raltegravir area under
small study of double-dose lopinavir–ritonavir in combi- the curve but not overcome the effect on concentration
nation with rifampicin-based antituberculosis treatment at 12 h after dosing [104].
in South Africa has shown the favourable outcomes, with In the phase II study, high rates of success were
80  % of patients achieving TB treatment success. How- achieved at 48 weeks with raltegravir 400 mg twice daily,
ever, 36 % of patients experienced gastrointestinal toxic- 800 mg twice daily, or efavirenz 600 mg once daily when
ity and 12 % had elevated liver enzymes [86]. used in combination with tenofovir and lamivudine in
In many resource-limited settings where HIV and TB patients receiving a rifampin-containing TB treatment
are epidemic, NNRTI-based ART remains a first-line [105]. However, further larger and long-term studies
regimen. Previous studies have shown some effects of remain needed to confirm this finding. Given rifampicin
rifampicin on the minimal efavirenz concentrations. lowers the minimum concentration of raltegravir, dou-
Some experts recommend increasing the dosage of efa- bling the dose of raltegravir to 800 mg twice daily should
virenz from 600 to 800  mg/day in patients with body be an appropriate treatment strategy. Studies examining
weight more than 50  kg to overcome the drug–drug the concomitant use of dolutegravir and rifampicin are
interactions [87]. Subsequent trials have shown that ongoing.
concomitant use of standard-dose efavirenz at 600  mg/ The rapid worldwide scale‐up of ART in the resource-
day and rifampicin does not compromise the clinical limited settings has led to increasing numbers of patients
treatment outcomes [88–92]. However, certain genetic failing first‐line ART. The options for second-line ART
polymorphisms of efavirenz metabolism, i.e., single after failure with a first-line NNRTI-based regimen gen-
nucleotide polymorphisms of the hepatic cytochrome erally involve the switch to a PI combined with an alter-
P450 isoenzyme 2B6 (CYP2B6) gene, have been associ- nate NRTI backbone. As aforementioned, the drug–drug
ated with high inter-patient variations in its plasma con- interactions between rifampicin and PIs are extensive.
centrations. The CYP 2B6 516G>T is associated with Therefore, rifabutin should be an appropriate alternative
high plasma concentrations even among patients con- rifamycin in this setting although clinical data regard-
currently receiving rifampicin [93–96]. Given its proven ing safety and efficacy in the treatment of TB in HIV-
efficacy and simplicity, the use of a standard dose of efa- infected patients is scanty. However, rifabutin is not
virenz at 600  mg/day combined with two NRTIs is the available in many countries and it is not produced in
recommended regimen in antiretroviral-naïve patients fixed dose combination. Thus, an alternative option is
who are receiving rifampicin. using a non-rifamycin anti-TB regimen in HIV-infected
Prior studies demonstrated that rifampicin reduces patients receiving PIs. Fluoroquinolones such as ofloxa-
plasma concentrations of nevirapine by 20–55 % [97–99]. cin, levofloxacin, or ciprofloxacin may be used to sub-
However, virological and immunological responses to stitute rifampicin. In addition, a non-rifamycin anti-TB
nevirapine-based ART when given at a dose of 200  mg regimen should be given for a period of 9–12  months.
twice daily were similar for patients that are and are not The management of HIV-infected patients taking PIs and
receiving rifampin-containing antituberculous treatment undergoing treatment for active TB with a non-rifamycin
[100]. Additionally, a 2-week lead-in period of nevirap- anti-TB regimen should be directed by, or conducted
ine is associated with a higher chance of virological fail- in consultation with, a physician with experience in the
ure owing to subtherapeutic concentration of nevirapine care of patients with these two diseases. This care should
[91]. Non-inferiority of the nevirapine-based ART was include close attention to the possibility of TB treatment
Manosuthi et al. AIDS Res Ther (2016) 13:22 Page 7 of 12

failure, antiretroviral treatment failure, and overlapping lasts for 2–3  months. However, late manifestations of
toxicities for all drugs used. IRIS may present. The common manifestations include
high fever, worsening of lymph node enlargement (Fig. 1),
Overlapping toxicities of antituberculous and antiretroviral and new or worsening of lung infiltration. The neurologi-
drugs cal TB IRIS may present with cerebral abscess, menin-
Adverse drug reactions occur more frequently among gitis, and radiculomyelitis [120, 121]. The identified risk
HIV-infected patients with TB who are receiving con- factors of paradoxical TB IRIS include low nadir CD4 cell
current treatment of HIV and TB than HIV-uninfected count at ART initiation [117, 122], extrapulmonary or
patients [106, 107]. The common overlapping toxicity disseminated TB [116, 123] and a short period between
profiles include liver toxicity, skin reactions, renal tox- starting TB treatment and ART [118]. The risk factors
icity, and gastrointestinal reactions [108–113]. Table  2 associated with death in paradoxical TB IRIS included a
shows the common overlapping adverse events of first- low nadir CD4 cell count prior to ART initiation and a
line antituberculous drugs and antiretroviral drugs. shorter period between initiating antituberculous treat-
These reactions may be complicated and need intensive ment and ART [48, 77].
management in some patients. Early recognition of these The second pattern, unmasking TB IRIS, occurs after
adverse events and prompt appropriate management of ART initiation in HIV-infected patients with undiag-
these problems can lead to successful integrated therapy nosed active TB. The subsequent immune restoration
in HIV-infected patients with TB. provokes the exaggerated symptoms of TB [124]. Thus,
the risk factor of unmasking TB IRIS relates to the effi-
TB IRIS ciency of TB screening and diagnosis of subclinical TB
TB IRIS may develop among HIV-infected patients who prior to ART initiation. A typical clinical presentation
had recently diagnosed active TB or had undiagnosed is rapid onset and clinical features of TB at the site of
TB and subsequently received effective ART. TB IRIS infection, such as high fever, pneumonitis, and lym-
or TB-associated immune recovery disease refers to an phadenitis [125, 126]. The symptoms may mimic bacte-
inflammatory reaction directed to M. tuberculosis anti- rial sepsis.
gen presenting at the sites of infection. Two patterns of The consensus case definition of both patterns of TB
TB IRIS have been described in the literatures, including IRIS is still debated because they do not provide clear
paradoxical TB IRIS and unmasking TB IRIS. The para- consensus on diagnosis [127–129]. The proposed defi-
doxical TB-IRIS is defined as the deterioration of existing nition of diagnosis in the resource-limited settings has
TB lesions after recent initiation, re-initiation or switch been published previously by the INSHI group [129].
to more effective ART. The patients with paradoxical TB However, patients with undiagnosed multidrug-resist-
IRIS typically have clinical improvement or clinical sta- ant TB may mimic the symptoms of paradoxical TB
bilization from receiving antituberculous treatment for IRIS. Thus, antituberculous drug resistance should be
a short period of time before initiating ART. The epide- excluded in all cases of suspected TB IRIS. In addition,
miologic data of paradoxical TB-IRIS are variable, rang- inadequate or inappropriate TB treatment, other concur-
ing from 8 to 42 % [114–118]. However, a meta-analysis rent opportunistic infections, and adverse drug reactions
showed that the frequency of paradoxical TB IRIS was need to be excluded. With regard to unmasking TB IRIS,
15.7 %, with a mortality rate of 3.2 % [119]. The onset of some residual immune deficiency leading to a new TB
paradoxical TB IRIS typically develops between 1 and and deterioration of subclinical TB disease may mimic
4  weeks after ART commencement and the symptoms unmasking TB IRIS [124].

Table 2  Common overlapping adverse events of first-line antituberculous drugs and antiretroviral drugs
Adverse events Antituberculous drugs Antiretroviral drugs Clinical characteristics

Skin reaction [108] Rifamycins, isoniazid, pyrazinamide, Nevirapine, efavirenz, abacavir Morbilliform rashes, Steven Johnson syn-
ethambutol, streptomycin drome and toxic epidermal necrolysis,
fixed drug eruption, lichenoid drug
eruptions and acute generalized exan-
thematous pustulosis
Liver toxicity [109–112] Rifamycins, isoniazid, pyrazinamide Nevirapine, efavirenz, protease inhibi- Transaminitis, cholestatic hepatitis
tors
Renal toxicity [113] Tenofovir Streptomycin, rifamycins Tubulo-interstitial nephritis, proximal
tubulopathy, acute renal failure
Manosuthi et al. AIDS Res Ther (2016) 13:22 Page 8 of 12

of infiltrating MTB-specific CD4+ T cells at the site of

infection [136].
Most cases of paradoxical TB IRIS are self-limited.
When mild paradoxical TB IRIS occurs, symptomatic
and supportive treatment can be given, including anal-
gesic drugs, anti-pyretic drugs, and anti-emetic drugs.
Local drainage of abscess may be required in some cases.
Nonsteroidal anti-inflammatory drugs can be used for
those cases in which inflammation or fever cause patients
discomfort. Moderate to severe TB IRIS may threaten
the clinical status of patients, such as neurologic seque-
lae from TB of central nervous system and decreased
pulmonary function of pulmonary TB IRIS. In such
cases, anti-inflammatory treatment should be consid-
ered. A randomized control trial showed that predniso-
lone at 1.5  mg/kg/day for 2  weeks followed by 0.75  mg/
kg/day for an additional 2 weeks resulted in a reduction
of hospitalization and therapeutic procedures [137]. In a
case series diagnosed with severe TB IRIS, time to symp-
tom improvement with prednisolone 10–80 mg/day was
3  days [118]. However, adverse effects of corticosteroid
treatment should be monitored. ART interruption is not
recommended because of increased risk of antiretroviral
drug resistance and developing of opportunistic infec-
tions. Other potential drugs used to treat TB IRIS are
Fig. 1  Paradoxical TB IRIS presenting as worsening of lymph node
thalidomide, leukotriene receptor antagonists, pentoxi-
enlargement fylline, and hydroxychloroquine [138].

Conclusions
Managing HIV and TB simultaneously is essential to
Three major factors involve the pathogenesis of TB- improve patients’ survival and quality of life. Integration
IRIS, including (1) mycobacterial antigen burden and of care for both HIV and TB using a single facility and
anti-TB treatment, (2) immune system function of the a single health care provider is a model to deliver inte-
patients, and (3) ART initiation and potency. The role grated therapy for both diseases and manage adverse
of mycobacterial antigen burden is suggested by the risk drug effects efficiently. Based on the evidence from ran-
of TB IRIS that is greater in the patients with earlier domized clinical trials and systemic review, various treat-
ART initiation during TB treatment when the residual ment guidelines have recommended early ART initiation.
mycobacterial load remains high and in those with dis- Integrated therapy is crucial for HIV-infected patients
seminated TB [124, 130]. Mycobacterial antigen releas- with TB. For TB treatment, a 2-month initial intensive
ing from the killing bacilli with TB treatment stimulates phase of isoniazid, rifampin, pyrazinamide, and etham-
an exuberant inflammatory response. The host immune butol, followed by 4  months of a continuation phase of
system also plays roles in the pathogenesis of TB IRIS. isoniazid and rifampin is considered as the standard
Pre-existing immune deficiency has been shown to pre- treatment of drug-susceptible TB. Rifabutin induces
dispose to TB IRIS. Many previous studies revealed that CYP3A activity at a lesser magnitude than rifampicin and
the low nadir CD4 cell counts have been related to sub- it may be a more appropriate option for co-administra-
sequent IRIS [119, 131, 132]. High plasma HIV viral load tion of many antiretroviral drugs, including PIs. How-
has been reported to be associated with TB IRIS [133]. ever, rifabutin is not available in many resource-limited
In addition, it is associated with an exuberant produc- countries—where HIV and TB are epidemic.
tion of inflammatory cytokines, such as IFN-gamma ART should be initiated in all HIV-infected patients
[134, 135]. In terms of ART, not only the rate of CD4 cell with TB, irrespective of CD4 cell count. The optimal
count recovery in peripheral blood after ART initiation is timing to commence ART in HIV-infected patients with
associated with TB IRIS [115], but the ART may also trig- TB is within the first 8 weeks of starting antituberculous
ger local immune reconstitution via increased numbers treatment and within the first 2  weeks for patients who
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Author details 16. Chaisson RE, Schecter GF, Theuer CP, Rutherford GW, Echenberg DF,
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