Management of HIV-associated Tuberculosis in Resource-Limited Settings: A State-Of-The-Art Review

Lawn et al.
BMC Medicine 2013, 11:253

http://www.biomedcentral.com/1741-7015/11/253
Medicine for Global Health
REVIEW Open Access
Management of HIV-associated tuberculosis in

resource-limited settings: a state-of-the-art review
Stephen D Lawn1,2,3*, Graeme Meintjes3,4, Helen McIlleron5, Anthony D Harries1,6 and Robin Wood2,3
Abstract
The HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited
settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major
progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early
diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy
of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living
with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis
and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled
trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment
with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions
and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution
inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing
HIV-associated drug-resistant TB.
Introduction management for individual patients with HIV-associated

The global epidemics of HIV/AIDS and tuberculosis (TB) TB and it has failed to control TB at a population level in
both remain huge challenges to international public health, settings with high HIV prevalence [2,7]. Comprehensive
causing illness and death in millions of people worldwide packages of additional interventions are needed to address
each year (Table 1) [1]. TB is the most important AIDS- the consequences of HIV in TB patients and to reduce the
related opportunistic disease globally and is the leading burden of TB in those living with HIV infection [8]. An in-
cause of HIV/AIDS-related mortality, accounting for an terim policy on collaborative TB/HIV activities was first
estimated 25% of such deaths [2,3]. Sub-Saharan Africa published by WHO in 2004 [9] and approximately 1.3 mil-
suffers disproportionately, with 79% of global cases of HIV- lion lives are estimated to have been saved by these inter-
associated TB [1]. In the countries of southern and eastern ventions by 2011 [1]. An updated policy (Table 2) [10]
Africa where HIV prevalence is highest, the impact of HIV published in 2012 provides the overall policy framework
has severely undermined TB control over the past 20 years for addressing HIV-associated TB and specific recommen-
[4]. The global co-epidemic has been further compounded dations on management of HIV, TB and multidrug-
in recent years by the emergence of the growing challenge resistant (MDR)-TB are provided by individual guideline
of multi-drug resistant TB (MDR-TB) [5,6]. documents [11-13] (Table 3).
The World Health Organization (WHO) DOTS (dir- This article provides an up-to-date review of the current
ectly observed treatment, short-course) TB control strat- medical management of adult patients with HIV-associated
egy used in isolation provides far from optimum case TB. We review case ascertainment as the critical first
step and then how clinical outcomes can be optimized
* Correspondence: [email protected]
1
by provision of effective TB treatment, use of concur-
Department of Clinical Research, Faculty of Infectious and Tropical Diseases,
London School of Hygiene and Tropical Medicine, Keppel Street, London
rent ART, prevention of HIV-related comorbidities and
WC1E 7HT, UK management of drug cotoxicity and immune reconsti-
2
The Desmond Tutu HIV Centre, Institute for Infectious Disease and tution inflammatory syndrome (IRIS). We also describe
Molecular Medicine, Faculty of Health Sciences, University of Cape Town,
Cape Town, South Africa
the management of HIV-associated MDR-TB. However,
Full list of author information is available at the end of the article the management of children, models of integrated TB and
© 2013 Lawn et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. 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.
Lawn et al. BMC Medicine 2013, 11:253 Page 2 of 16
Table 1 Burden of HIV infection, tuberculosis (TB) and HIV-associated TB globally and in sub-Saharan Africa
Disease Global burden Burden in sub-Saharan Africa: (% of global burden)
HIV/AIDS:
No. of people living with HIV infection 34,200,000 23,500,000 (69%)
HIV/AIDS-related deaths 1,700,000 1,200,000 (71%)
Tuberculosis:
No. of incident cases of TB 8,700,000 2,300,000 (26%)
TB deaths (excluding HIV) 990,000 220,000 (22%)
Incident cases of multidrug-resistant TB 310,000 45,000 (15%)
HIV-associated tuberculosis:
No. of incident cases 1,100,000 870,000 (79%)
No. of HIV-associated TB deaths 430,000 300,000 (70%)
Data from [1,3]. Incident disease and deaths represent annual disease burden.
HIV care delivery and prevention of TB in people living Africa over the past 20 years have repeatedly shown that
with HIV using ART and isoniazid preventive therapy lie between 30% and 50% of HIV-infected adult inpatients
outside the scope of this review. who die have postmortem evidence of TB, much of which
was neither clinically suspected nor diagnosed before
Diagnosis of HIV-associated TB death [14-17]. These studies have highlighted the abject
The prerequisite for optimum management of HIV- failure of the diagnostic process and the low sensitivity of
associated TB is early and accurate diagnosis and, for diagnostic tools available [18]. In the absence of more sen-
many years, this has been a key obstacle. Case ascertain- sitive means of diagnosis, management algorithms for sus-
ment can be greatly improved by high rates of quality- pected sputum smear-negative disease were developed
assured HIV testing among those being investigated for [19-21] and studies of empirical TB treatment for certain
TB as well as high rates of screening for TB in those liv- high risk patient groups with advanced immunodeficiency
ing with HIV. are being conducted [22].
However, in recent years there have been significant
Screening for TB in those living with HIV infection advances in screening and diagnosis. Traditional symptom
In high burden settings, much prevalent TB disease re- screening for pulmonary TB based on chronic cough
mains ‘below the radar’ in those living with HIV. Postmor- has low sensitivity for HIV-associated TB [23,24]. A new
tem studies conducted in hospitals across sub-Saharan WHO symptom screening tool for HIV-associated TB
Table 2 World Health Organization (WHO)-recommended collaborative tuberculosis (TB)/HIV activities (adapted from [10])
Key area Points of action
Establish and strengthen the mechanisms for Set up and strengthen a coordinating body for collaborative TB/HIV activities
delivering integrated TB and HIV services
Determine the HIV prevalence among TB patients and the TB prevalence among
HIV patients
Carry out joint TB/HIV planning to integrate the delivery of TB and HIV services
Monitor and evaluate collaborative TB/HIV activities
Reduce the burden of TB in people living with Intensify TB case finding and ensure high quality TB treatment
HIV (early ART plus the three Is)
Initiate TB prevention using isoniazid preventive therapy and early antiretroviral
therapy (ART)
Ensure control of TB infection in healthcare facilities and congregate settings
Reduce the burden of HIV in patients with diagnosed Provide HIV testing and counseling to both groups of patients
TB and those under investigation for TB
Provide HIV preventive interventions to both groups of patients
Provide co-trimoxazole preventive therapy for TB patients living with HIV
Provide HIV prevention interventions, treatment and care for TB patients living
with HIV
Provide antiretroviral therapy for TB patients living with HIV
Table 3 World Health Organization (WHO) policy guidelines on collaborative tuberculosis (TB)/HIV activities and the
management of HIV infection, TB and multidrug-resistant TB (MDR-TB)
Guidelines/year Details Reference
Guidelines for collaborative TB/HIV activities (2012) World Health Organization. WHO policy on collaborative TB/HIV activities. [10]
Guidelines for national programmes and stakeholders. 2012. World Health
Organization, Geneva. WHO/HTM/TB/2012.1. http://whqlibdoc.who.int/
publications/2012/9789241503006_eng.pdf
Antiretroviral treatment guidelines (2013) World Health Organization. Consolidated guidelines on the use of antiretroviral [11]
drugs for treating and preventing HIV infection. Recommendations for a public
health approach, June 2013. WHO, Geneva. Accessible at: http://apps.who.
int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf.
Tuberculosis treatment guidelines (2010) World Health Organization. Treatment of tuberculosis: guidelines - fourth edition. [12]
World Health Organization, Geneva, 2010. WHO/HTM/TB/2009.420 Accessible
at: http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf
Drug-resistant TB treatment guidelines (2011) World Health Organization. Guidelines for the management of drug-resistant [13]
tuberculosis: 2011 update. WHO, Geneva. WHO/HTM/TB/2011.6. Accessible at:
http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf.
(one or more of the following symptoms: cough, fever, (CD4 counts <200 cells/μl) following admission to hospital
weight loss or night sweats, each of any magnitude or dur- or enrolling in ART clinics [28,31].
ation) has much higher sensitivity and is recommended
for routine screening of those in HIV care at each visit Screening for HIV in those with TB or possible TB
[25]. However, in view of its low specificity, further re- A major step forward in improving HIV testing rates in
search is needed to define which of the large number of patients with TB was the switch from voluntary counseling
patients with a positive screen should be prioritized for and testing (VCT) to provider-initiated testing and coun-
subsequent microbiological testing of clinical samples. seling (PITC) in 2007 [33]. With PITC, all patients
New diagnostic tools have also increased our capacity undergo routine testing unless they specifically opt out.
for microbiological diagnosis. This includes the Xpert Testing has increased globally from 3.1% in 2004 to 40%
MTB/RIF assay, which was endorsed by WHO in 2010. A of notified TB cases in 2011, but falls well short of the goal
single test is able to detect all sputum smear-positive dis- of universal testing [1]. Testing rates have reached 69% in
ease, approximately 70% of smear-negative pulmonary dis- Africa, >50% in the Americas and 32% in South-East Asia.
ease and provides rapid simultaneous screening for RIF In African countries, the proportion of TB patients testing
resistance [26]. In addition, this assay can be used to test a positive is 46% overall (range, 8% to 77%) and exceeds
wide range of extrapulmonary sample types [26,27]. The 50% in ten counties in the south and east of the continent
Xpert MTB/RIF assay has been incorporated into the na- [1]. A further significant policy change has been to expand
tional guidelines of many high burden countries. In South PITC to include all patients being investigated for TB re-
Africa, which alone accounts for approximately 30% of the gardless of whether or not TB is diagnosed [10,12]. This
global burden of HIV-associated TB, sputum smear mi- change resulted from the observed high HIV prevalence
croscopy has now been replaced by Xpert MTB/RIF as the and mortality among those presenting for investigation of
initial diagnostic test for TB [26]. possible TB even when this diagnosis was subsequently ex-
Determine TB-LAM is a low-cost, point-of-care lateral- cluded [34]. It is critical, however, that improved testing
flow (‘strip test’) assay that diagnoses TB through detection rates are accompanied by improvement in the delivery of
in urine of lipoarabinomannan (LAM): a lipopolysaccharide appropriate management.
component of the M. tuberculosis cell wall [28]. It has
high specificity whereas sensitivity is very strongly CD4 Optimized TB treatment
count dependent, at best detecting approximately two- The first priority for patients with HIV-associated TB is to
thirds of cases in those with CD4 counts <50 cells/μl immediately start effective TB treatment using a regimen
[28-31]. This assay therefore allows rapid (<30 minutes) containing RIF throughout [12,35]. A systematic review
bedside diagnosis among those who have the highest found that the incidence of relapse and/or failure among
mortality risk [32]. The growing evidence base on this patients treated with intermittent (thrice weekly) TB ther-
assay will be reviewed by WHO in 2014. Its role is likely apy throughout was two to three times higher than that in
to be as an add-on test within the diagnostic algorithm to patients who received a daily intensive phase [36]. Thus,
permit point-of-care diagnosis and immediate TB treat- the recommended optimum standard regimen is 2 months
ment among patients with advanced immunodeficiency of rifampicin, isoniazid, pyrazinamide and ethambutol
followed by 4 months of rifampicin and isoniazid (2HRZE/ Plan to Stop TB, 2011-2015 [46]. Evidence is unclear as
4HR), with therapy administered daily throughout [12]. to whether co-trimoxazole should be continued indefin-
Where this is not possible, an acceptable alternative is to itely or might be discontinued once the CD4 cell count
use a thrice-weekly continuation phase. Treatment out- has reached a threshold of either 200 or 350 cells/μl [11].
comes are worse for those with isoniazid monoresistance The potential benefits of ongoing therapy may vary ac-
[36,37] and, thus, in settings with high prevalence of iso- cording to local factors such as the safety of the water
niazid monoresistance, 2HRZE/4HRE is the recommended supply, the presence of malaria and the local spectrum of
first-line regimen [12]. Drug susceptibility testing is rec- opportunistic pathogens.
ommended to guide treatment in patients who have previ-
ously been treated for TB, although ideally all patients Antiretroviral treatment
with TB should have drug susceptibility testing. Where the In observational cohort studies, concurrent ART reduces
Xpert MTB/RIF assay is being rolled out as the primary mortality risk by 64% to 95% in patients receiving treat-
TB diagnostic test, RIF resistance screening is now integral ment for HIV-associated TB [47]. In the South African
to the initial diagnostic process [26]. Starting Antiretroviral Therapy at Three Points in Tu-
After several decades with no new advances in TB treat- berculosis Therapy (SAPIT) randomized trial, receipt of
ment, there are now some promising developments. For concurrent ART was associated with survival benefit
example, several large-scale phase III randomized con- among those with CD4 cell counts of <200 cells/μl and
trolled trials (including the ReMOX, Oflotub and RIFA- 200 to 500 cells/μl [48]. Recommended first-line ART
QUIN studies) are evaluating whether incorporation of a regimens for use with TB treatment are based on non-
newer fluoroquinolone into treatment regimens can be nucleoside reverse transcriptase inhibitors (NNRTI),
used to shorten treatment for drug susceptible TB [38]. with efavirenz (EFV) as the preferred choice and nevira-
The first of these to report, the RIFAQUIN study, found pine (NVP) as an alternative. While first-line regimen
treatment shortening was associated with a higher rate of choices are well established, second-line ART remains
adverse outcomes including failure, relapse and death [39]. problematic. The recommended regimens and their
However, none of these studies have been designed to spe- pharmacokinetic interactions with TB treatment are
cifically address this question in HIV-infected clinical pop- shown in Table 5 and the hiv-druginteractions.org web-
ulations. There is also a growing developmental pipeline site provides a useful up-to-date source of information
of new TB drugs, although these are most likely to be used on interactions (see [49]). Combining the multidrug reg-
in the treatment of MDR-TB, at least initially [38]. imens used to treat TB and HIV is complicated not only
by high pill burden and increased risks of drug-drug in-
Co-trimoxazole preventive therapy teractions, but also by cotoxicity and immune reconsti-
Co-trimoxazole (trimethoprim sulfamethoxazole) is a low- tution inflammatory syndrome (IRIS).
cost, widely available and relatively safe antibiotic that re-
duces morbidity and mortality in people living with HIV Pharmacokinetic interactions with first-line ART
due to prophylactic activity against a range of pathogens, Although RIF induces the expression of cytochrome
including those causing bacterial sepsis, pneumocystis P450 2B6 (CYP2B6), which comprises the main meta-
pneumonia, cerebral toxoplasmosis and malaria. Both ob- bolic pathway for EFV, studies have failed to demon-
servational and randomized controlled trials conducted in strate significantly reduced concentrations of EFV with
sub-Saharan Africa have shown that this simple interven- concomitant RIF-based TB treatment [50-53]. This is
tion is associated with a substantial reduction in mortality consistent with the observed virological responses which
among patients with HIV-associated TB (range, 19% to are excellent in patients receiving RIF-based TB treat-
46%) [40-44] (Table 4). This beneficial effect was observed ment treated with standard 600 mg daily doses of EFV
in a range of settings with high or low rates of bacterial re- [54-57] and were better than those in TB patients ran-
sistance to the drug and is additive in reducing early mor- domized to NVP-based ART in the recent CARINEMO
tality when combined with ART [45]. trial [56]. Similarly, lowering the dose of EFV to 400 mg
Routine administration of co-trimoxazole to patients daily in the ENCORE1 trial did not compromise out-
with HIV-associated TB is recommended (480 mg comes in non-TB patients [58]. Thus, although the US
twice per day or 960 mg once per day) [10-12]. Imple- Federal Drug Administration (FDA) [59] recommends
mentation of this simple, life-saving intervention has that the dose of EFV during RIF treatment is increased
steadily increased from a negligible proportion in 2004 in adults weighing more than 50 kg, this is not sup-
to 79% of all notified TB cases with a positive HIV test ported by studies in TB patients [53] and is not recom-
in 2011 (79% of those in the African region and 89% of mended by the WHO for resource-limited settings.
those in the South-East Asian region) [1]. Coverage Conversely, however, among patients with a slow
needs to increase to the 100% target set in the Global CYP2B6 metabolizer genotype, EFV concentrations are
Table 4 Impact of co-trimoxazole prophylaxis on mortality among predominately adult patients with HIV-associated
tuberculosis (TB)
Study Year of publication Study design Country Level of bacterial No. of study Mortality
resistance to participants reduction
co-trimoxazole
Wiktor et al. [40] 1999 Randomized controlled trial Cote D’Ivoire Low 771 46%
Zachariah et al. [41] 2003 Cohort study (‘before’ and ‘after’ Malawi (north) High 1,986 19%
study with historical controls)
Mwaungulu et al. [42] 2004 Cohort study (‘before’ and ‘after’ Malawi (south) High 717 22%
Grimwade et al. [43] 2005 Cohort study (‘before’ and ‘after’ South Africa High 3,325 29%
Nunn et al. [44] 2008 Randomized controlled trial Zambia High 1,003 21%
increased during TB treatment, possibly due to inhib- NVP-based ART remains inferior to EFV-based regi-
ition by INH of accessory pathways metabolizing EFV mens in TB patients [56]. During the 14-day lead-in
[60,61]. This genotype is relatively common in Africa, phase of NVP dosing, plasma drug concentrations are
South-East Asia, and the Caribbean [50-52,62,63]. Whether very low in patients receiving RIF, potentially predispos-
EFV-induced central nervous system (CNS) adverse ef- ing to the development of viral resistance mutations and
fects are more frequent during TB treatment or isoniazid contributing to an increased risk of virological failure
preventive therapy in patients with this genotype needs to [54]. The CARENIMO trial recently found that NVP
be evaluated. was well tolerated when introduced at full doses (200
NVP is a reasonably safe, acceptable alternative for TB mg twice a day) in patients with CD4 cell counts <250
patients unable to tolerate EFV. Through induction of cells/mm3 receiving RIF [56]. The use of a dose escal-
the expression of CYP2B6, RIF treatment reduces NVP ation lead-in phase to avoid toxicity in patients receiving
concentrations by an average of approximately 40% and RIF is therefore not recommended.
Table 5 Approaches to cotreatment for HIV-infected patients with rifampicin-susceptible tuberculosis

Combined regimens Treatment recommendations Drug-drug interactions
Efavirenz + rifampicin-based No dose adjustments TDF + 3TC/FTC + EFV Rifampicin induces CYP2B6 but inhibition of CYP2A6 by
TB treatment (WHO-recommended optimum regimen) isoniazid might account for increased efavirenz
AZT + 3TC + EFV (alternative WHO regimen) concentrations during TB treatment in those patients with
slow CYP2B6 metabolizer genotype
Nevirapine + rifampicin-based Omit 14 day lead-in phase of once daily dose of Rifampicin induces CYP2B6 and CYP3A4. Although TB
TB treatment NVP TDF + 3TC/FTC + NVP (alternative WHO regimen) treatment reduces nevirapine concentrations, toxicity
AZT + 3TC + NVP (alternative WHO regimen) concerns curtail increasing the dose and outcomes are
acceptable (but inferior to EFV) on standard doses.
Lopinavir/ritonavir + rifampicin- Double dose lopinavir/ritonavir (800/200 mg Rifampicin induces CYP3A4, p-glycoprotein and OATP1B1.
based TB treatment 12 hourly) Or superboost lopinavir (lopinavir/ Ritonavir counteracts this effect and adjusted doses of
ritonavir 400/400 mg 12 hourly) Monitor alanine ritonavir or lopinavir/ritonavir are used to compensate, but
transaminase (ALT) closely. lopinavir concentrations may be more variable. Increased
risk of hepatotoxicity, and gastrointestinal side effects.
PI/ritonavir + rifabutin-based Reduce rifabutin dose to 150 mg daily or thrice Ritonavir-boosted PIs markedly increase rifabutin
TB treatment weekly. Monitor closely for rifabutin toxicity. concentrations and reduce its clearance necessitating
reduction in the dose of rifabutin by 50% to 75%. Toxicity
(neutropenia, uveitis, hepatoxicity, rash, gastrointestinal
symptoms) and suboptimal rifamycin exposures with
reduced dose are concerns.
Triple nucleoside/tide regimen + No dose adjustments. A triple nucleoside/tide Triple nucleoside/tide regimens may perform adequately in
rifampicin-based TB treatment regimen should include tenofovir or abacavir. patients with viral suppression who have not failed a first
Monitor viral load. line regimen, and provide alternative ART regimens in
patients with contraindications to efavirenz or nevirapine,
wehre other options are unavailable. TB treatment has
minimal effect on tenofovir concentrations. Although
rifampicin induces the enzymes responsible for
glucuronidation of abacavir and zidovudine, this effect is
not thought to be clinically important.
3TC 2′,3′-dideoxy-3′-thiacytidine, ART antiretroviral therapy, CYP cytochrome P450, EFV efavirenz, FTC emtricitabine, OATP organic anion-transporting polypeptide,
NNRTI non-nucleoside reverse transcriptase inhibitor, NVP nevirapine, PI protease inhibitor, TB tuberculosis, TDF tenofovir, WHO World Health Organization.
Triple nucleoside/tide regimens are less effective than recommend a daily 150 mg dose of rifabutin for patients
NNRTI-based or PI-based regimens particularly in pa- on ritonavir-boosted PIs [85].
tients with baseline viral loads >100,000 copies/ml [64]. There is extremely limited information about the
However, small uncontrolled studies suggest they may safety or efficacy using rifabutin with PIs and this may
provide an acceptable regimen for TB patients who have vary between populations due to differential increases in
not failed an ART regimen [65,66] even though the con- rifabutin concentrations. Severe neutropenia and uveitis
centrations of abacavir and zidovudine may be reduced occur relatively frequently in patients with increased ex-
by concomitant RIF. This therefore provides an alterna- posures [81,86] and hepatitis, gastrointestinal symptoms,
tive option for those in whom EFV and NVP are contra- rashes and anemia are also important safety concerns
indicated and integrase inhibitors unavailable. [87,88]. While rifabutin is becoming more widely avail-
able and affordable, it is not an ideal solution for high
Pharmacokinetic interactions with second-line ART burden settings where limited patient monitoring is
With increasing numbers of patients switching to prote- available and fixed dose drug formulations are preferred.
ase inhibitor (PI)-based second-line ART regimens, de- Thus, there is an urgent need for research to define the
fining safe and effective approaches to concurrent TB optimum approaches for the cotreatment of patients
treatment is an urgent challenge. The pharmacokinetic with TB who have failed first-line ART, including the use
interactions between rifamycins and PIs are extensive. of newer agents.
RIF reduces concentrations of ritonavir-boosted PIs by
75% to 90% [67]. Conversely, through potent inhibition Pharmacokinetic interactions with newer ART drugs
of CYP3A4 and p-glycoprotein, high-dose ritonavir off- Ritonavir-boosted darunavir has a favorable safety and
sets the effect of RIF-mediated induction such that tolerability compared to lopinavir/ritonavir and promis-
‘superboosting’ of lopinavir or saquinavir (lopinavir/rito- ing efficacy, especially in treatment of ART-experienced
navir 400 mg/400 mg or saquinavir/ritonavir 400 mg/ patients. A pharmacokinetic study in healthy volunteers
400 mg, twice daily) preserves plasma concentrations of suggests that it could be used in standard doses with
the PI [68-70]. Adequate plasma concentrations of lopi- rifabutin 150 mg thrice weekly, but the drug-drug inter-
navir are also achieved in adults by doubling the dose of actions with RIF have not been studied. Integrase inhibi-
lopinavir/ritonavir in the tablet formulation (to 800/200 tors have potent antiviral activity and are well tolerated,
mg twice daily); this is the simplest approach, especially but any future role in ART programs in low-resource
in settings where the separate ritonavir is not available settings is at present undefined. However, initial data on
[71]. Although these approaches are associated with use with TB treatment show promise. Pharmacokinetic
high rates of hepatotoxicity in studies of healthy volun- studies suggest that doubling the dose of raltegravir to
teers, these seem to be much safer in HIV infected pa- 800 mg twice daily compensates for the effect of RIF on
tients [71-76]. Nevertheless, hepatotoxicity, gastrointestinal overall exposure [89,90] and this approach seems to be
side effects and poor tolerability are problematic and well tolerated and effective in patients with HIV-
treatment discontinuation rates of up to nearly 50% have associated TB [91]. However, preliminary results of the
been reported [74,75]. REFLATE TB study suggest that such dose adjustment
Rifabutin is an alternative rifamycin to RIF, but data may not even be necessary as virological responses were
on its use in TB patients receiving ritonavir-boosted PIs similar in ART-naive TB patients receiving RIF who
are limited. Studies of healthy volunteers show that were randomized to receive 400 mg or 800 mg of ralte-
ritonavir-boosted PIs increase the concentrations of rifa- gravir twice daily or EFV daily [92]. Similar to raltegravir,
butin approximately fourfold and the concentrations of a pharmacokinetic study of dolutegravir in healthy vol-
the active metabolite to an even greater extent. Thus, unteers suggests that the effect of RIF on antiretroviral
the dose of rifabutin needs to be reduced. Thrice weekly therapy can be overcome by increasing the daily 50 mg
150 mg doses of rifabutin in combination with standard dose of dolutegravir to 50 mg twice daily and that dose
doses of lopinavir/ritonavir may be reasonably tolerated adjustment may not be necessary with rifabutin [93].
[77,78]. However, contrary to expectations based on
pharmacokinetic data from healthy volunteers, small Timing of ART initiation during TB treatment
studies in coinfected patients have found that rifabutin The optimum time to start ART in patients with HIV-
150 mg used thrice weekly in combination with lopina- associated TB is subject to a complex series of competing
vir/ritonavir resulted in low rifabutin concentrations risks [94] and must balance the high risk of morbidity
[79-82]. Such levels would be conducive to acquisition and mortality in patients with very low CD4 cell counts
of rifamycin resistance in patients with severe immuno- and severe disease with the potential occurrence of
suppression [79,83] as has been observed with twice additive toxicities and immune reconstitution inflam-
weekly doses [84]. Thus, recent US national guidelines matory syndrome (IRIS). Results of large randomized
strategy trials are now available to inform guidelines recommended ART regimens [101,102]. HIV infection
(Table 6) [48,55,95-98]. Patients with baseline CD4 itself has been identified as a risk factor for DILI in pa-
counts of <200 and 200 to 500 cells/μl have improved tients receiving TB treatment in some [103,104] but not
survival benefit from coadministered ART [48] and all studies [105-108]. Of the currently used ART drugs,
WHO recommends that ART be given to all patients NVP is associated with highest risk of DILI; however,
concurrently with TB treatment regardless of the CD4 EFV and PIs are also recognized causes.
count. Trial data also demonstrated that mortality was Concurrent TB treatment in patients receiving NNRTI-
reduced in those with the most severe immunodeficiency based ART has been associated with an increased risk of
(CD4 cell counts <50 cells/μl) if they stated ART within DILI in some [109-111] but not all [54] studies. In one of
the first 2 weeks of TB treatment [11]. For patients with these, the absolute risk of severe hepatotoxicity in patients
less severe immunosuppression (CD4 counts >50 cells/μl), receiving EFV-based ART was low, but the risk associated
data suggested that ART might be deferred until com- with concurrent TB treatment exceeded that associated
pletion of the intensive phase of TB treatment without with positive hepatitis B surface antigen status [109]. Im-
compromising survival but reducing the risk of morbid- portantly, a randomized trial of NVP-based versus EFV-
ity from TB-IRIS [55,96]. based ART in patients receiving TB treatment reported
WHO guidelines reflect these findings, recommending more treatment discontinuations related to DILI in the
that TB treatment should be started first and followed NVP arm (4 vs 0%) [56].
by ART as soon as possible within the first 8 weeks of Development of DILI significantly complicates man-
treatment but within the first 2 weeks for those with agement of HIV-associated TB. Elevation of alanine
profound immunosuppression (CD4 count <50 cells/μl) transaminase (ALT) concentrations >3 to 5 times the
[11]. However, CD4 count measurements may either upper limit of normal especially when accompanied by
be unavailable or be inaccurate in some settings. In symptoms or jaundice requires that all potentially hep-
addition, within different CD4 count categories, there is atotoxic medication is interrupted until derangements of
great diversity in severity of disease and mortality risk. liver function tests resolve. Thereafter, rechallenge of
Thus, where feasible, decisions on timing for individual first-line TB medication should be considered followed
patients might also be further informed by taking into by ART, although rechallenge is generally not under-
account clinical criteria such as body mass index, Karnofsky taken if there was liver failure. Rechallenge strategies
score, severity of anemia and extent of TB. Moreover, have not been studied in randomized trials in HIV-
national guidelines might best be appropriately tailored infected patients. However, in the largest randomized
for operational simplicity. One possible option, for ex- trial of TB without HIV coinfection, approximately 90%
ample, might be to start ART in all patients after 2 of patients were rechallenged with their first-line TB
weeks of TB treatment, accepting lower risk of mortal- drugs without recurrence [112]. Risk of recurrence was
ity but higher risk of TB IRIS. not related to whether the four first-line TB drugs were
Patients with HIV-associated TB meningitis represent reintroduced sequentially or concurrently. Further stud-
an important exception. A randomized trial from Viet ies are needed to define the optimum rechallenge strat-
Nam found no survival benefit from early ART in pa- egy in coinfected patients in whom both TB treatment
tients with TB meningitis [97], reflecting the awful prog- and ART require reintroduction. Until further evidence
nosis (mortality approximately 60%) of these patients emerges, the American Thoracic Society recommends
with advanced disease and the dire consequences of TB- that RIF can be reintroduced in coinfected patients once
IRIS within the confined space of the CNS [99]. Further the ALT is less than two times the upper limit of normal
studies are required in different geographical settings to followed by reintroduction of INH with monitoring of
better define appropriate management of these patients. liver function [100]. However, they also suggest that pyr-
azinamide is not reintroduced.
Adverse drug reactions and management While some cohort studies have suggested low mor-
Antituberculosis and antiretroviral drugs have overlapping bidity and mortality in HIV-infected patients with DILI
toxicity profiles that include drug-induced liver injury [109], mortality is substantial among those requiring
(DILI), cutaneous reactions, renal impairment, neuropathy hospital admission. In a South African study, mortality
and neuropsychiatric adverse effects (Table 7). These com- was 35% among patients admitted to hospital with DILI
plicate management in a substantial minority of patients. during TB treatment, ART or concurrent therapy [113].
In patients without coinfection, DILI (variably defined Reasons for these deaths were sepsis and liver failure, al-
as, for example, an elevation of alanine aminotransferase though interruption of required TB treatment and ART
to >3 or >5 times the upper limit of the normal range) are likely to have played a role.
occurs in 5% to 33% of those receiving TB treatment TB treatment is associated with a spectrum of cutane-
[100] and in 5% to 11% of those receiving currently ous adverse reactions including morbiliform rashes,
Lawn et al. BMC Medicine 2013, 11:253
Table 6 Randomized controlled studies of the timing of starting antiretroviral therapy (ART) during tuberculosis (TB) treatment
Study Study population Methods Results
N Location TB Median CD4+ Timing of ART Primary Follow-up Primary endpoint Primary endpoint TB immune
cells/mm3 (IQR) in weeks ‘earlier’ endpoint in months ‘earlier’ vs ‘later’a in CD4 <50 cells/μlb reconstitution
vs ‘later’
SAPIT [48] (first analysis) 429 South Africa Smear-positive 150 (77 to 254) <12 vs after end Death 12.1 5.4 vs 12.1 Not reported 12.4% vs 3.8%
pulmonary TB TB treatment P = 0.003c P <0.001
SAPIT [96] (second 429 South Africa Smear-positive 150 (77 to 254) Within 4 vs 8 AIDS or death 17.7 6.9 vs 7.8 8.5 vs 26.3b 20.1% vs 7.7%
analysis) pulmonary TB to 12 P = 0.73 P = 0.06 P <0.001
CAMELIA [95] 660 Cambodia Smear-positive TB 25 (11 to 56) 2 vs 8 Death 25 18% vs 27%, Not reportedd 33.1% vs 13.7%
P = 0.006 P <0.001
STRIDE [55] 809 Multicontinente Confirmed or 77 (36 to 145) 2 vs 8 to 12 AIDS or death 12 12.9% vs 16.1% 15.5% vs 26.6% 11% vs 5%
presumed P = 0.45 P = 0.02 P = 0.02
pulmonary or
extrapulmonary TB
TB Meningitis [97] 253 Vietnam TB meningitis 39 (18 to 116) ≤1 vs 8 Deathf 12 59.8% vs 55.6% 63.3% vs 65.1% Not reported
P = 0.50 P = 0.84
TIME Trial [98] 156 Thailand Confirmed or 43 (37 to 106) 4 vs 12 Death 96 weeks 7.6% vs 6.5% 8.7% vs 13.1% 8.86 vs 5.02
presumed P >0.99 P = 0.725 P = 0.069
pulmonary or
extrapulmonary TB
Footnotes:
a
Presented either as cumulative incidence of primary endpoint in early vs. later arm (%) or as events per 100 person-years.
b
Prespecified analysis.
c
Significant difference in mortality observed in patients with either CD4 counts <200 cells/μl or 200 to 500 cells/μl.
d
Lower CD4 was not associated with an increased risk for the primary endpoint.
e
North America, South America, Asia, Africa.
f
Primary endpoint was all cause mortality at 9 months.
Page 8 of 16
Table 7 Shared side effects of antiretroviral therapy (ART) and antituberculosis drugs
Adverse effects Antiretroviral drugs Antituberculosis drugs
Gastrointestinal disturbance and/or pain AZT, ddI, PIs RIF, INH, PZA, ethionamide, PAS, clofazamine, linezolid
a
Liver injury NVP, EFV, PIs, NRTIs RIF, INH, PZA and many second line drugs including
ethionamide, fluoroquinolones, PAS
Peripheral neuropathy D4T, ddI INH, ethionamide, terizidone/cycloserine, linezolid
Neuropsychiatric EFV Terizidone/cycloserine, ethionamide, fluoroquinolones, INH
Renal impairment TDF Aminoglycosides and capreomycin
Rash NVP, EFV, ABC Rifampicin, INH, PZA, ethambutol, streptomycin and many
second line drugs including fluoroquinolones, PAS, clofazamine
Blood dyscrasias AZT, 3TC Linezolid, rifabutin, INH, rifampicin
Cardiac conduction abnormalities PIs Bedaquiline, fluoroquinolones, clofazamine
Pancreatitis D4T, ddI Linezolid
Lactic acidosis D4T, ddI Linezolid
3TC 2',3'-dideoxy-3'-thiacytidine, ABC abacavir, AZT zidovudine, D4T stavudine, ddI didanosine, EFV efavirenz, INH isoniazid, NRTIs nucleoside reverse transcriptase
inhibitors, NVP nevirapine, PAS para-aminosalicylic acid, PIs protease inhibitors, PZA pyrazinamide, RIF rifampicin, TDF tenofovir.
a
NRTIs (especially D4T and ddI) can cause steatohepatitis.
Steven Johnson syndrome and toxic epidermal necrolysis, paradoxical TB IRIS and unmasking TB-IRIS and case
fixed drug eruption, lichenoid drug eruptions and acute definitions have been published [120]. Paradoxical TB-
generalized exanthematous pustulosis [114]. Cotrimoxa- IRIS is an important cause of morbidity in patients
zole, NVP, and to a lesser extent EFV, can also cause many known to have HIV-associated TB and occurs within the
of the same clinical presentations [102,115,116]. HIV coin- first weeks of ART [120,121]. The typical clinical course
fection was associated with a fivefold increased risk of rash of paradoxical TB-IRIS is as follows. Initiation of TB
or drug fever in one study [117] but small, non-significant treatment in a patient with HIV infection and newly di-
increases in risk in others [105,108]. If a clinically signifi- agnosed TB results in clinical stabilization or improve-
cant rash develops, all potentially responsible drugs need ment. However, subsequent introduction of ART is
to be interrupted and then a carefully monitored rechal- accompanied by recurrence or exacerbation of TB symp-
lenge of first-line TB drugs can be considered once the toms with new or worsening clinical signs of TB that
rash has resolved. In a cohort of mainly HIV-infected pa- often have a marked inflammatory component [120,121].
tients rechallenged following cutaneous reactions to TB While seldom life-threatening, deaths due to paradox-
drugs, 50% developed reintroduction reactions but only a ical TB-IRIS have been described. Two major risk factors
small minority were severe [118]. identified in observational studies [122-125] and in clin-
Renal dysfunction may be caused via different mecha- ical trials [55,95,126] are a low CD4 count prior to ART
nisms in patients receiving tenofovir, RIF or aminoglyco- and a shorter interval between starting TB treatment
sides (used for MDR-TB). Tenofovir and aminoglycosides and ART. There is no diagnostic test for TB-IRIS; the
may both cause tubular cell toxicity at the level of the diagnosis is based on clinical presentation and exclusion
proximal renal tubules, whereas RIF infrequently causes a of alternative diagnoses such as bacterial infection or
tubulointerstitial nephritis mediated by immune hypersen- drug resistant TB [120]. However, drug-resistant TB is
sitivity. Case reports describe renal failure in patients re- not only in the differential diagnosis as an alternative
ceiving a combination of tenofovir and aminoglycosides, cause of the clinical deterioration but may also be a risk
although cohort studies have not confirmed an increased factor for the development of paradoxical TB-IRIS [127].
risk [119]. The combination is best avoided when possible. The second major form of TB-IRIS is commonly re-
In patients with significant renal dysfunction, Use of teno- ferred to as ‘unmasking’ TB-IRIS. This occurs when ac-
fovir should be avoided where possible and dosing of eth- tive TB is present but remains undiagnosed at the time
ambutol, NRTI drugs, some quinolones (ofloxacin and of starting ART [120,128]. Subsequent immune recovery
levofloxacin) and certain other second-line antituberculo- triggers the overt symptomatic presentation of TB. In a
sis drugs (including cycloserine, para-aminosalicylic acid, proportion of cases, unusual inflammatory features may
clofazamine and linezolid) needs to be adjusted. also develop and such cases are regarded as having
‘unmasking’ TB-IRIS. Risk of unmasking TB-IRIS is
TB Immune reconstitution inflammatory syndrome (IRIS) therefore directly related to the efficiency of the pre-
Two major forms of TB immune reconstitution syn- ART screening process and the resulting prevalence of
drome (TB-IRIS) are recognized and these are called undiagnosed disease.
Both types of TB IRIS have a wide range of clinical fea- CNS. A subgroup of patients in this trial (approximately
tures often with involvement of multiple organ systems, one in five) relapsed after stopping prednisone and re-
reflecting widespread dissemination of M. tuberculosis in quired a further and more prolonged course to control
those with profound immunosuppression. Common fea- symptoms [134]. Similarly, in other settings, TB-IRIS has
tures include fever, recurrence of respiratory symptoms relapsed in up to 50% of patients after stopping steroids
with worsening infiltrates on chest radiographs, enlarge- [133] and thus the duration of therapy must be tailored ac-
ment of lymph nodes (often with suppuration), formation cording to the clinical response.
of tuberculous abscesses and serous effusions [120,121]. Non-steroidal anti-inflammatory drugs (NSAIDs) have
There are many case reports of unusual and diverse com- also been used in the treatment of TB IRIS although no
plications, including granulomatous nephritis with renal clinical trial data exist to support their use. Other forms
impairment, parotitis, epididymo-orchitis, granulomatous of immunomodulatory therapy such as thalidomide, aza-
hepatitis, splenic enlargement and abscess formation, psoas thioprine and tumor necrosis factor α blockers (such as
abscess, peritonitis, ascites and intestinal involvement adalumimab) have been used in cases refractory to ster-
[120,121]. Neurological TB-IRIS is particularly severe, man- oid therapy with anecdotal reports of benefit [135]. In
ifesting with tuberculomas, tuberculous abscesses, cerebral patients with suppurative lymphadenitis or abscesses,
edema, meningitis and radiculomyelopathy [99,129,130]. needle aspiration may provide a pus sample to exclude
Neurological TB IRIS has a much poorer outcome com- drug-resistant TB as well as bringing symptomatic relief.
pared to other forms, with a mortality of 13% to 75% There is no evidence base for pharmacological pre-
[99,129,130]. vention of TB-IRIS. However, this needs to be consid-
In most cases, the onset of paradoxical TB-IRIS is ered in view of the recommendation within guidelines
within the first 4 weeks of ART (median 14 days (IQR, 8 for early ART initiation in TB patients with advanced
to 23) in 1 series [127]) but can occur within a few days. HIV [11]. Adjunctive immunomodulatory therapies might
The proportion of patients affected ranges widely from reduce the risk or severity of TB-IRIS in such patients.
0% to over 40% [120] and this may relate to differences A randomized placebo-controlled trial of prednisone
in risk factors and case definitions. In a meta-analysis, for prevention of TB-IRIS in high-risk patients (CD4
the summary risk estimate was 15.7% [131]. Of these, counts <100 cells/mm3 starting ART within 30 days of
3.2% died, representing approximately 1 in 200 patients TB treatment) is underway [136]. Until results from
with HIV-associated TB who start ART. The median this trial are available corticosteroids cannot be recom-
duration of TB-IRIS symptoms has been reported to be mended for prevention of TB IRIS with the exception
2 to 3 months [124,125] but a minority of cases have a of patients with TB of the CNS for whom adjunctive
protracted course which may last for more than 1 year steroids form part of the standard of care [137]. How-
[120,124,132]. Such protracted cases typically have per- ever, in such patients, TB IRIS occurs in approximately
sistent or recurrent suppurative lymphadenitis or abscess 50% of patients with CNS TB starting ART despite re-
formation. However, the majority of cases have a favor- ceipt of corticosteroids [99].
able long-term outcome [133]. Other agents that have been proposed for prevention
TB-IRIS is not an indication for stopping ART, although of TB IRIS are vitamin D, statins and the C-C chemo-
this should be considered in life-threatening cases such as kine receptor type 5 (CCR5) blocker maraviroc [135].
those with cerebral edema and depressed level of con- Vitamin D has modulating effects on both the adaptive
sciousness or severe respiratory failure. In mild cases, no and innate immune responses [138,139]. Statins have
specific treatment is usually required; the patient should anti-inflammatory properties and there is precedence for
be treated symptomatically and counseled regarding the using these agents for autoimmune inflammatory disor-
need to continue ART and TB treatment. Corticosteroids ders in an experimental model [140,141]. However, nei-
should be considered if symptoms are more significant. ther vitamin D nor statins have yet been tested in
In a randomized placebo-controlled trial, prednisone clinical studies. Maraviroc, however, was shown not to
used at a dose of 1.5 mg/kg/day for 2 weeks followed prevent IRIS in a placebo-controlled trial conducted in
by 0.75 mg/kg/day for 2 weeks was associated with re- Mexico and South Africa [142].
duced morbidity (duration of hospitalization and need for
therapeutic procedures) [134]. Symptom improvement Management of HIV-associated MDR-TB
was more rapid and there was no excess risk of other se- The emergence of MDR-TB and extensively drug resistant
vere infections [134]. Although no mortality benefit was TB (XDR-TB) has compounded the HIV-associated TB
demonstrated, patients with immediately life-threatening epidemic in resource-limited settings [5,143]. MDR-TB is
TB-IRIS were not enrolled in view of ethical consider- caused by strains that are resistant to both rifampicin and
ations. Indeed, most experts recommend steroid therapy isoniazid whereas XDR-TB strains are MDR-TB strains
for life-threatening TB-IRIS, especially IRIS involving the with additional resistance to any quinolone drug and any
one of the second-line injectable aminoglycosides (amika- symptoms, peripheral neuropathy, hypothyroidism, deafness,
cin, capreomycin or kanamycin). Much disease remains psychiatric symptoms and hypokalemia [148,149]. In up
undiagnosed due to lack of laboratory capacity. However, to 40% of patients these adverse events are severe
increasing implementation of the Xpert MTB/RIF assay [148]. This relates to the inherent toxicity associated
now provides the means for rapid screening for RIF re- with MDR drugs; it does not appear that HIV-infected
sistance, although follow-on testing is then required to patients experience a higher incidence of adverse events
further characterize the full drug susceptibility pattern. than HIV-uninfected patients, nor that coadministration
This can be performed phenotypically through culture- with ART increases toxicity [148,150,151].
based systems but is very slow. In 2008, WHO approved Antiretroviral drugs do share common toxicities with
the use of line probe assays for the rapid molecular detec- second-line antituberculosis drugs, however (Table 7).
tion of drug resistance in smear-positive specimens or cul- Some of the most challenging of these are neuropsychi-
ture isolates [144] and a range of commercially available atric side effects. EFV causes inattention, vivid dreams
assays now offer the possibility of much more rapid diag- and dizziness in up to 50% of patients, but in a minority
nosis of both MDR-TB and XDR-TB [145]. However, these can be severe with mood disturbance or psychosis.
line-probe assays can only be used where appropriate la- Cycloserine (or terizidone) is a well recognized cause of
boratory facilities and expertise exist as they are highly psychosis, seizures and other CNS side effects although
technically demanding and are well beyond the scope of several other drugs such as the quinolones, ethionamide
most resource-limited settings apart from in specialized and high dose isoniazid can also cause CNS side effects.
reference laboratories. If patients develop severe CNS side effects it may be ne-
Worldwide, successful treatment of MDR-TB is achieved cessary to withdraw all possible culprit drugs with care-
in only approximately 50% to 60% of patients [146,147], ful sequential reintroduction once resolved. Cycloserine
but management is considerably more difficult in resource- should probably be regarded as the most likely culprit
limited settings and especially in those with HIV coin- for psychosis and seizures. Antipsychotic or antidepres-
fection due to late diagnosis with more frequent extra- sant medications may be required. EFV should not be
pulmonary dissemination, high risks of drug cotoxicity routinely avoided because the majority of MDR-TB pa-
and IRIS, copathology and poor adherence with pro- tients tolerate it well.
longed, toxic regimens. The WHO recommends that Much research is needed on how to improve treatment
patients with confirmed MDR-TB should receive a for drug-resistant TB. A shortened MDR-TB regimen of 9
regimen containing pyrazinamide together with at months, which was found to be effective and well tolerated
least four second-line drugs in the intensive phase that in Bangladesh [152], is now being evaluated in Ethiopia,
are likely to be effective, including a fluoroquinolone South Africa and Vietnam and includes patients with
(using a later generation agent where possible), a par- HIV-associated TB. In the future, the newly approved
enteral agent (such as amikacin or kanamycin), ethi- agent bedaquiline (TMC-207) as well as two new nitroimi-
onamide (or prothionamide) and either cycloserine or dazoles (PA-824 and delaminid (OPC67683) under evalu-
p-aminosalicylic acid (PAS) [13]. An intensive phase of 8 ation) may offer the prospects of improved treatment for
months and a total treatment duration of 20 months is sug- MDR-TB [38]. However, a prolonged timeline is needed
gested for most patients, but may be modified according to to adequately define how to combine existing agents
response. A range of other second-line drugs that have lim- and new drugs in regimens that optimize outcomes and
ited efficacy may be used for treatment of XDR-TB and that can be combined with ART in those with HIV-
treatment regimens should be based upon drug susceptibil- associated TB.
ity testing [13]. However, evidence to inform best practice
is lacking and outcomes are often poor. Conclusions
Co-trimoxazole prophylaxis and ART are recom- The HIV-associated TB epidemic is a major challenge
mended for all patients with HIV-associated MDR-TB to international public health, remaining the most im-
regardless of CD4 count and the timing of ART initi- portant opportunistic infection in people living with
ation is similar as for drug-susceptible TB [11]. Many of HIV globally and accounting for nearly 0.5 million
the second-line MDR-TB drugs are poorly tolerated and deaths each year. However, over the past 10 years,
drug discontinuation rates are high as a result of adverse major progress has been achieved in defining guidelines
effects. MDR-TB may be a risk factor for TB IRIS in for the optimum case management with a combination
view of slow mycobacterial antigen clearance [127]. Nu- of co-trimoxazole prophylaxis, optimally timed ART,
tritional depletion and co-morbid conditions may further and diagnosis and appropriate supportive care for treat-
undermine outcomes. ment complications including drug toxicity and IRIS.
Adverse events are frequent in HIV-infected patients receiv- The major remaining challenges are the management
ing MDR treatment, the most common being gastrointestinal of TB in the increasing proportion of patients receiving
PI-containing ART and the management of drug resistant 9. World Health Organization: Interim Policy on Collaborative TB/HIV activities. Who/
TB. Having defined case management strategies, the HTM/TB/2004.330 WHO/HTM/HIV/2004.1. Geneva, Switzerland: WHO; 2004.
10. World Health Organization: WHO Policy on Collaborative TB/HIV Activities.
ongoing challenge is to further develop effective, com- Guidelines for National Programmes and Stakeholders. Geneva, Switzerland:
prehensive and sustainable means of delivery through World Health Organization; 2012.
health systems. 11. World Health Organization: Consolidated Guidelines on the Use of
Antiretroviral Drugs for Treating and Preventing HIV Infection.
Abbreviations Recommendations for a Public Health Approach, June 2013. Geneva,
ALT: alanine transaminase; ART: antiretroviral treatment; CNS: central nervous Switzerland: World Health Organization; 2013.
system; CYP: cytochrome P450 enzyme; E: ethambutol; EFV: efavirenz; 12. World Health Organization: Treatment of Tuberculosis: Guidelines - Fourth
H/INH: isoniazid; IRIS: immune reconstitution inflammatory syndrome; Edition. Geneva, Switzerland: World Health Organization; 2010.
LAM: lipoarabinomannan; MDR-TB: multidrug resistant tuberculosis; 13. World Health Organization: Guidelines for the Management of Drug-Resistant
NNRTI: non-nucleoside reverse transcriptase inhibitor; NVP: nevirapine; Tuberculosis: 2011 Update. Geneva, Switzerland: World Health Organization; 2011.
PI: protease inhibitor; PITC: provider initiated counseling and testing; 14. Lucas SB, Hounnou A, Peacock C, Beaumel A, Djomand G, N’Gbichi JM,
R/RIF: rifampicin; TB: tuberculosis; VCT: voluntary counseling and testing; Yeboue K, Honde M, Diomande M, Giordano C: The mortality and
WHO: World Health Organization; XDR-TB: extensively drug resistant pathology of HIV infection in a west African city. AIDS 1993, 7:1569–1579.
tuberculosis; Z: pyrazinamide. 15. Rana FS, Hawken MP, Mwachari C, Bhatt SM, Abdullah F, Ng’ang’a LW,
Power C, Githui WA, Porter JD, Lucas SB: Autopsy study of HIV-1-positive
Competing interests and HIV-1-negative adult medical patients in Nairobi, Kenya. J Acquir
The authors declare they have no competing interests. Immune Defic Syndr 2000, 24:23–29.
16. Ansari NA, Kombe AH, Kenyon TA, Hone NM, Tappero JW, Nyirenda ST,
Authors’ contributions Binkin NJ, Lucas SB: Pathology and causes of death in a group of 128
The first draft was written by SDL, GM and HMcI. All authors contributed to predominantly HIV-positive patients in Botswana, 1997–1998. Int J Tuberc
the development of subsequent and final drafts. All authors approved the Lung Dis 2002, 6:55–63.
final version. 17. Cohen T, Murray M, Wallengren K, Alvarez GG, Samuel EY, Wilson D: The
prevalence and drug sensitivity of tuberculosis among patients dying in
Acknowledgments hospital in KwaZulu-Natal, South Africa: a postmortem study. PLoS Med
SDL is funded by the Wellcome Trust, London, UK. 2010, 7:e1000296.
18. Reid MJ, Shah NS: Approaches to tuberculosis screening and diagnosis in
Author details people with HIV in resource-limited settings. Lancet Infect Dis 2009,
1
Department of Clinical Research, Faculty of Infectious and Tropical Diseases, 9:173–184.
London School of Hygiene and Tropical Medicine, Keppel Street, London 19. World Health Organization: Improving the Diagnosis and Treatment of Smear-
WC1E 7HT, UK. 2The Desmond Tutu HIV Centre, Institute for Infectious Negative Pulmonary and Extra-Pulmonary Tuberculosis among Adults and Ado-
Disease and Molecular Medicine, Faculty of Health Sciences, University of lescents. Recommendations for HIV-Prevalent and Resource-Constrained Set-
Cape Town, Cape Town, South Africa. 3Department of Medicine, Faculty of tings. WHO/HTM/2007.379 & WHO/HIV/2007.1. Geneva, Switzerland: World
Health Sciences, University of Cape Town, Cape Town, South Africa. 4Clinical Health Organization; 2007.
Infectious Diseases Research Initiative, Institute of Infectious Disease and 20. Holtz TH, Kabera G, Mthiyane T, Zingoni T, Nadesan S, Ross D, Allen J,
Molecular Medicine, University of Cape Town, Cape Town, South Africa. Chideya S, Sunpath H, Rustomjee R: Use of a WHO-recommended algo-
5
Division of Clinical Pharmacology, Department of Medicine, Faculty of rithm to reduce mortality in seriously ill patients with HIV infection and
Health Sciences, University of Cape Town, Cape Town, South Africa. smear-negative pulmonary tuberculosis in South Africa: an observational
6
International Union against Tuberculosis and Lung Disease (The Union), cohort study. Lancet Infect Dis 2011, 11:533–540.
Paris, France. 21. Wilson D, Nachega J, Morroni C, Chaisson R, Maartens G: Diagnosing
smear-negative tuberculosis using case definitions and treatment
Received: 3 September 2013 Accepted: 7 November 2013 response in HIV-infected adults. Int J Tuberc Lung Dis 2006, 10:31–38.
Published: 02 Dec 2013 22. Lawn SD, Ayles H, Egwaga S, Williams B, Mukadi YD, Santos Filho ED,
Godfrey-Faussett P, Granich RM, Harries AD: Potential utility of empirical
References tuberculosis treatment for HIV-infected patients with advanced immuno-
1. World Health Organization: Global Tuberculosis Control Report 2012. Geneva: deficiency in high TB-HIV burden settings. Int J Tuberc Lung Dis 2011,
World Health Organization; 2012. 15:287–295.
2. Lawn SD, Churchyard G: Epidemiology of HIV-associated tuberculosis. Curr 23. Cain KP, McCarthy KD, Heilig CM, Monkongdee P, Tasaneeyapan T, Kanara
Opin HIV AIDS 2009, 4:325–333. N, Kimerling ME, Chheng P, Thai S, Sar B, Phanuphak P, Teeratakulpisarn N,
3. WHO/UNAIDS: Global HIV/AIDS Response. Epidemic Update and Health Sector Phanuphak N, Nguyen HD, Hoang TQ, Le HT, Varma J: An algorithm for
Progress Towards Universal Access. Progress report 2011. http://www.unaids. tuberculosis screening and diagnosis in people with HIV. N Engl J Med
org/en/media/unaids/contentassets/documents/unaidspublication/2011/ 2010, 362:707–716.
20111130_UA_Report_en.pdf. 2011. 24. Lawn SD, Wood R: Tuberculosis in antiretroviral treatment services in
4. Lawn SD, Zumla AI: Tuberculosis. Lancet 2011, 378:57–72. resource-limited settings: addressing the challenges of screening and
5. Wells CD, Cegielski JP, Nelson LJ, Laserson KF, Holtz TH, Finlay A, Castro KG, diagnosis. J Infect Dis 2011, 204:S1159–S1167.
Weyer K: HIV infection and multidrug-resistant tuberculosis: the perfect 25. Getahun H, Kittikraisak W, Heilig CM, Corbett EL, Ayles H, Cain KP, Grant AD,
storm. J Infect Dis 2007, 196:S86–S107. Churchyard GJ, Kimerling M, Shah S, Lawn SD, Wood R, Maartens G, Granich
6. Abubakar I, Zignol M, Falzon D, Raviglione M, Ditiu L, Masham S, Adetifa I, R, Date AA, Varma J: Development of a standardized screening rule for
Ford N, Cox H, Lawn SD, Marais BJ, McHugh TD, Mwaba P, Bates M, Lipman tuberculosis in people living with HIV in resource-constrained settings:
M, Zijenah L, Logan S, McNerney R, Zumla A, Sarda K, Nahid P, Hoelscher M, individual participant data meta-analysis of observational studies. PLoS
Pletschette M, Memish ZA, Kim P, Hafner R, Cole S, Migliori GB, Maeurer M, Med 2011, 8:e1000391.
Schito M: Drug-resistant tuberculosis: time for visionary political 26. Lawn SD, Mwaba P, Bates M, Piatek A, Alexander H, Marais BJ, Cuevas LE,
leadership. Lancet Infect Dis 2013, 13:529–539. McHugh TD, Zijenah L, Kapata N, Abubakar I, McNerney R, Hoelscher M,
7. De Cock KM, Chaisson RE: Will DOTS do it? A reappraisal of tuberculosis Memish ZA, Migliori GB, Kim P, Maeurer M, Schito M, Zumla A: Advances in
control in countries with high rates of HIV infection. Int J Tuberc Lung Dis tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects
1999, 3:457–465. for a point-of-care test. Lancet Infect Dis 2013, 13:349–361.
8. Harries AD, Zachariah R, Corbett EL, Lawn SD, Santos-Filho ET, Chimzizi R, 27. World Health Organization: Roadmap for Rolling out Xpert Mtb/Rif for Rapid
Harrington M, Maher D, Williams BG, De Cock KM: The HIV-associated Diagnosis of TB and MDR-TB. Geneva, Switzerland: World Health
tuberculosis epidemic–when will we act? Lancet 2010, 375:1906–1919. Organization; 2010.
28. Lawn SD: Point-of-care detection of lipoarabinomannan (LAM) in urine 47. Lawn SD, Kranzer K, Wood R: Antiretroviral therapy for control of the HIV-
for diagnosis of HIV-associated tuberculosis: a state of the art review. associated tuberculosis epidemic in resource-limited settings. Clin Chest
BMC Infect Dis 2012, 12:103. Med 2009, 30:685–699.
29. Lawn SD, Kerkhoff AD, Vogt M, Wood R: Diagnostic accuracy of a low-cost, 48. Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray A,
urine antigen, point-of-care screening assay for HIV-associated pulmon- Gengiah T, Nair G, Bamber S, Singh A, Khan M, Pienaar J, El-Sadr W, Fried-
ary tuberculosis before antiretroviral therapy: a descriptive study. land G, Abdool Karim Q: Timing of initiation of antiretroviral drugs during
Lancet Infect Dis 2012, 12:201–209. tuberculosis therapy. N Engl J Med 2010, 362:697–706.
30. Peter JG, Theron G, Zyl-Smit R, Haripersad A, Mottay L, Kraus S, Binder A, 49. hiv-druginteractions.org: Homepage. [http://www.hiv-druginteractions.org].
Meldau R, Hardy A, Dheda K: Diagnostic accuracy of a urine lipoarabino- 50. Cohen K, Grant A, Dandara C, McIlleron H, Pemba L, Fielding K,
mannan strip-test for TB detection in HIV-infected hospitalised patients. Charalombous S, Churchyard G, Smith P, Maartens G: Effect of rifampicin-
Eur Respir J 2012, 40:1211–1220. based antitubercular therapy and the cytochrome P450 2B6 516G>T
31. Lawn SD, Dheda K, Kerkhoff AD, Peter JG, Dorman S, Boehme CC, Nicol M: polymorphism on efavirenz concentrations in adults in South Africa.
Determine TB-LAM lateral flow urine antigen assay for HIV-associated Antivir Ther 2009, 14:687–695.
tuberculosis: recommendations on the design and reporting of clinical 51. Uttayamakul S, Likanonsakul S, Manosuthi W, Wichukchinda N, Kalambaheti
studies. BMC Infect Dis 2013, 13:407. T, Nakayama EE, Shioda T, Khusmith S: Effects of CYP2B6 G516T
32. Lawn SD, Kerkhoff AD, Vogt M, Wood R: Clinical significance of polymorphisms on plasma efavirenz and nevirapine levels when
lipoarabinomannan detection in urine using a low-cost point-of-care co-administered with rifampicin in HIV/TB co-infected Thai adults.
diagnostic assay for HIV-associated tuberculosis. AIDS 2012, 26:1635–1643. AIDS Res Ther 2010, 7:8.
33. World Health Organization/UNAIDS: Guidance on Provider-Initiated HIV 52. Ngaimisi E, Mugusi S, Minzi O, Sasi P, Riedel KD, Suda A, Ueda N, Janabi M,
Testing and Counselling in Health Facilities. Geneva, Switzerland: WHO/ Mugusi F, Haefeli WE, Bertilsson L, Burhenne J, Aklillu E: Effect of rifampicin
UNIADS; 2007. and CYP2B6 genotype on long-term efavirenz autoinduction and plasma
34. Kumar AM, Gupta D, Gupta RS, Satyanarayana S, Wilson S, Zachariah R, exposure in HIV patients with or without tuberculosis. Clin Pharmacol
Lawn SD, Harries AD: HIV testing in people with presumptive Ther 2011, 90:406–413.
tuberculosis: time for implementation. Lancet Respir Med 2013, 1:7–9. 53. Luetkemeyer AF, Rosenkranz SL, Lu D, Marzan F, Ive P, Hogg E, Swindells S,
35. Jindani A, Nunn AJ, Enarson DA: Two 8-month regimens of chemotherapy Benson CA, Grinsztejn B, Sanne IM, Havlir DV, Aweeka F, Adult AIDS, Clinical
for treatment of newly diagnosed pulmonary tuberculosis: international Trials Group A5221 Study Team: Relationship between weight, efavirenz
multicentre randomised trial. Lancet 2004, 364:1244–1251. exposure, and virologic suppression in HIV-infected patients on
36. Menzies D, Benedetti A, Paydar A, Martin I, Royce S, Pai M, Vernon A, rifampin-based tuberculosis treatment in the AIDS clinical trials group
Lienhardt C, Burman W: Effect of duration and intermittency of rifampin A5221 STRIDE study. Clin Infect Dis 2013, 57:586–593.
on tuberculosis treatment outcomes: a systematic review and meta- 54. Boulle A, Van CG, Cohen K, Hilderbrand K, Mathee S, Abrahams M,
analysis. PLoS Med 2009, 6:e1000146. Goemaere E, Coetzee D, Maartens G: Outcomes of nevirapine- and
37. Menzies D, Benedetti A, Paydar A, Royce S, Madhukar P, Burman W, Vernon efavirenz-based antiretroviral therapy when coadministered with
A, Lienhardt C: Standardized treatment of active tuberculosis in patients rifampicin-based antitubercular therapy. JAMA 2008, 300:530–539.
with previous treatment and/or with mono-resistance to isoniazid: a sys- 55. Havlir DV, Kendall MA, Ive P, Kumwenda J, Swindells S, Qasba SS, Luetkemeyer
tematic review and meta-analysis. PLoS Med 2009, 6:e1000150. AF, Hogg E, Rooney JF, Wu X, Hosseinipour MC, Lalloo U, Veloso VG, Some FF,
38. Zumla A, Nahid P, Cole ST: Advances in the development of new Kumarasamy N, Padayatchi N, Santos BR, Reid S, Hakim J, Mohapi L, Mugyenyi
tuberculosis drugs and treatment regimens. Nat Rev Drug Discov 2013, P, Sanchez J, Lama JR, Pape JW, Sanchez A, Asmelash A, Moko E, Sawe F,
12:388–404. Andersen J, Sanne I, et al: Timing of antiretroviral therapy for HIV-1 infection
39. Jindani A, et al: A Multicentre Randomized Clinical Trial to Evaluate High-dose and tuberculosis. N Engl J Med 2011, 365:1482–1491.
Rifapentine with a Quinolone for Treatment of Pulmonary TB: The RIFAQUIN 56. Bonnet M, Bhatt N, Baudin E, Silva C, Michon C, Taburet AM, Ciaffi L, Sobry
Trial. Atlanta, USA: Program and abstracts of the 20th Conference on A, Bastos R, Nunes E, Rouzioux C, Jani I, Calmy A, CARINEMO study group:
Retroviruses and Opportunistic Infections; 2013. Abstract #147LB. Nevirapine versus efavirenz for patients co-infected with HIV and
40. Wiktor SZ, Sassan-Morokro M, Grant AD, Abouya L, Karon JM, Maurice C, tuberculosis: a randomised non-inferiority trial. Lancet Infect Dis 2013,
Djomand G, Ackah A, Domoua K, Kadio A, Yapi A, Combe P, Tossou O, Roels 13:303–312.
TH, Lackritz EM, Coulibaly D, De Cock KM, Coulibaly IM, Greenberg AE: Effi- 57. Lawn SD, Myer L, Bekker LG, Wood R: Burden of tuberculosis in an
cacy of trimethoprim-sulphamethoxazole prophylaxis to decrease mor- antiretroviral treatment programme in sub-Saharan Africa: impact on
bidity and mortality in HIV-1-infected patients with tuberculosis in treatment outcomes and implications for tuberculosis control. AIDS 2006,
Abidjan, Cote d’Ivoire: a randomised controlled trial. Lancet 1999, 20:1605–1612.
353:1469–1475. 58. Puls R, The ENCORE1 Study Group: A daily dose of 400mg efavirenz (EFV) is
41. Zachariah R, Spielmann MP, Chinji C, Gomani P, Arendt V, Hargreaves NJ, non-inferior to the standard 600mg dose: week 48 data from the ENCORE1
Salaniponi FM, Harries AD: Voluntary counselling, HIV testing and study, a randomised, double-blind, placebo controlled, non-inferiority trial.
adjunctive co-trimoxazole reduces mortality in tuberculosis patients in Abstract WELBB01. Kuala Lumpur, Malaysia: 7th International AIDS Society
Thyolo, Malawi. AIDS 2003, 17:1053–1061. Conference on HIV Pathogenesis, Treatment and Prevention 2013, IAS 2013.
42. Mwaungulu FB, Floyd S, Crampin AC, Kasimba S, Malema S, Kanyongoloka 59. Federal Drug Administation (FDA): Sustiva labeling update/dosing
H, Harries AD, Glynn JR, Fine PE: Co-trimoxazole prophylaxis reduces adjustment with rifampin. [http://www.fda.gov/ForConsumers/ByAudience/
mortality in human immunodeficiency virus-positive tuberculosis ForPatientAdvocates/HIVandAIDSActivities/ucm294476.htm].
patients in Karonga District, Malawi. Bull World Health Organ 2004, 60. Kwara A, Lartey M, Sagoe KW, Court MH: Paradoxically elevated efavirenz
82:354–363. concentrations in HIV/tuberculosis-coinfected patients with CYP2B6
43. Grimwade K, Sturm AW, Nunn AJ, Mbatha D, Zungu D, Gilks CF: 516TT genotype on rifampin-containing antituberculous therapy. AIDS
Effectiveness of co-trimoxazole prophylaxis on mortality in adults with 2011, 25:388–390.
tuberculosis in rural South Africa. AIDS 2005, 19:163–168. 61. McIlleron HM, Schomaker M, Ren Y, Sinxadi P, Nuttall JJ, Gous H, Moultrie H,
44. Nunn AJ, Mwaba P, Chintu C, Mwinga A, Darbyshire JH, Zumla A: Role of Eley B, Merry C, Smith P, Haas DW, Maartens G: Effects of rifampin-based
co-trimoxazole prophylaxis in reducing mortality in HIV infected adults antituberculosis therapy on plasma efavirenz oncentrations in children
being treated for tuberculosis: randomised clinical trial. BMJ 2008, vary by CYP2B6 genotype. AIDS 2013, 27:1933–1940.
337:a257. 62. Ramachandran G, Ramesh K, Hemanth Kumar AK, Jagan I, Vasantha M,
45. Lowrance DW, Makombe S, Harries AD, Shiraishi RW, Hochgesang M, Berle- Padmapriyadarsini C, Narendran G, Rajasekaran S, Swaminathan S:
Grasse J, Libamba E, Schouten E, Ellerbrock T, Kamoto K: A public health Association of high T allele frequency of CYP2B6 G516T polymorphism
approach to rapid scale-up of antiretroviral treatment in Malawi during among ethnic south Indian HIV-infected patients with elevated plasma
2004–2006. J Acquir Immune Defic Syndr 2008, 49:287–293. efavirenz and nevirapine. J Antimicrob Chemother 2009, 63:841–84.
46. World Health Organization: The Global Plan to STOP TB 2011–2015. Geneva, 63. Leger P, Dillingham R, Beauharnais CA, Kashuba AD, Rezk NL, Fitzgerald DW,
Switzerland: World Health Organization; 2010. Pape JW, Haas DW: CYP2B6 variants and plasma efavirenz concentrations
during antiretroviral therapy in Port-au-Prince, Haiti. J Infect Dis 2009, 81. Naiker S, Conolly C, Weisner L, Phillips D, Harries A, Lienhardt C, McIlleron H,
200:955–964. Pym A: Pharmacokinetic Evaluation of Different Rifabutin Dosing Strategies in
64. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA African TB Patients on Lopinavir/ritonavir-based ART [abstract 650]. Boston,
3rd, Acosta EP, Schackman BR, Pilcher CD, Murphy RL, Maher WE, Witt MD, MA: Program and abstracts of the 18th Conference on Retroviruses and
Reichman RC, Snyder S, Klingman KL, Kuritzkes DR, AIDS Clinical Trials Group Opportunistic Infections; 2011.
Study A5095 Team: Triple-nucleoside regimens versus efavirenz- 82. Huy Dung N, Barrail-Tran A, Thi Ngoc Lan N, Hong Duc N, Thi Nguyet Thu N,
containing regimens for the initial treatment of HIV-1 infection. N Engl J Ngoc Lan N, Laureillard D, Thi Xuan Lien T, Borand L, Quillet C, Connolly C,
Med 2004, 350:1850–1861. Lagarde D, Pym A, Lienhardt C, Taburet A-M, Harries AD: Rifabutin Pharmacokin-
65. Srikantiah P, Walusimbi MN, Kayanja HK, Mayanja-Kizza H, Mugerwa RD, Lin etics when Coadministered with Lopinavir/Ritonavir in HIV-infected Patients with
R, Charlebois ED, Boom WH, Whalen CC, Havlir DV: Early virological Tuberculosis in Vietnam: results of ANRS12150b Cross-over Clinical Trial [abstract
response of zidovudine/lamivudine/abacavir for patients co-infected WEPE470]. 7th IAS Conference on HIV Pathogenesis and Treatment
with HIV and tuberculosis in Uganda. AIDS 2007, 21:1972–1974. (Kuala Lumpur). Geneva, Switzerland: International AIDS Society; 2013.
66. Shao H, Crump J, Ramadhani H, Uiso L, Sendui-Nguyaine O, Kiwera R, et al: 83. Jenny-Avital ER, Joseph K: Rifamycin-resistant Mycobacterium tuberculosis
A randomised trial of early versus delayed fixed dose combination zidovudine/ in the highly active antiretroviral therapy era: a report of 3 relapses with
lamivudine/abacavir in patients coinfected with HIV and tuberculosis: early acquired rifampin resistance following alternate-day rifabutin and
findings of the tuberculosis and immune reconstitution syndrome trial. Abstract boosted protease inhibitor therapy. Clin Infect Dis 2009, 48:1471–1474.
#796.Denver, CO: Abstracts of the 13th Conference on Retroviruses and 84. Weiner M, Benator D, Burman W, Peloquin CA, Khan A, Vernon A, Jones B,
Opportunistic Infections; 2006. Silva-Trigo C, Zhao Z, Hodge T: Association between acquired rifamycin
67. Loeliger A, Suthar AB, Ripin D, Glaziou P, O'Brien M, Renaud-Thery F, Crowley S, resistance and the pharmacokinetics of rifabutin and isoniazid among
Williams B, Ridzon R, Granich R, Gilks C: Protease inhibitor-containing patients with HIV and tuberculosis. Clin Infect Dis 2005, 40:1481–1491.
antiretroviral treatment and tuberculosis: can rifabutin fill the breach? 85. Department of Health and Human Services, Panel on antiretroviral
Int J Tuberc Lung Dis 2012, 16:6–15. guidelines for adults and adolescents: Guidelines for the use of
68. Veldkamp AI, Hoetelmans RM, Beijnen JH, Mulder JW, Meenhorst PL: antiretroviral agents in HIV-1-infected adults and adolescents.
Ritonavir enables combined therapy with rifampin and saquinavir. [http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf].
Clin Infect Dis 1999, 29:1586. 86. Moultrie H, McIlleron H, Sawry S, Kellermann T, Wiesner L, Kindra G, Gous H,
69. la Porte CJ, Colbers EP, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, Van Rie A: High Rate of Neutropenia in Young Children Receiving Concomitant
Koopmans PP, Hekster YA, Burger DM: Pharmacokinetics of adjusted-dose Ribabutin and Lopinavir/Ritonavir [abstract 993]. Seattle, WA: Program and
lopinavir-ritonavir combined with rifampin in healthy volunteers. abstracts of the 19th Conference on Retroviruses and Opportunistic
Antimicrob Agents Chemother 2004, 48:1553–1560. Infections; 2012.
70. Rolla VC, Silva Vieira MA, Pereira PD, Lourenco MC, De Jesus CS, Goncalves 87. Ng J, Nada A, Freeman S, Chiu YL, Cohen D, Bernstein B, Awni W, Klein C:
MM, Ferreira FM, Werneck-Barroso E: Safety, efficacy and pharmacokinetics Pharmacokinetics of RIFABUTIN 150 mg TIW plus Lopinavir/Ritonavir (LPV/r)
of ritonavir 400mg/saquinavir 400mg twice daily plus rifampicin 400/100 mg Bid Administered in Healthy Adult Subjects (abstract O_21).
combined therapy in HIV patients with tuberculosis. Clin Drug Investig Amsterdam, The Netherlands: 10th International Workshop on Clinical
2006, 26:469–479. Pharmacology of HIV Therapy; 2009.
71. Decloedt EH, McIlleron H, Smith P, Merry C, Orrell C, Maartens G: 88. Sekar V, Lavreys L, de CT V, Berckmans C, Spinosa-Guzman S, Vangeneugden
Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin T, De Pauw M, Hoetelmans R: Pharmacokinetics of darunavir/ritonavir and
with adjusted doses of lopinavir-ritonavir tablets. Antimicrob Agents rifabutin coadministered in HIV-negative healthy volunteers. Antimicrob
Chemother 2011, 55:3195–3200. Agents Chemother 2010, 54:4440–4445.
72. L’homme RF, Nijland HM, Gras L, Aarnoutse RE, van Crevel R, Boeree M, Brinkman 89. Wenning LA, Hanley WD, Brainard DM, Petry AS, Ghosh K, Jin B, Mangin E,
K, Prins JM, Juttmann JR, Burger DM: Clinical experience with the combined Marbury TC, Berg JK, Chodakewitz JA, Stone JA, Gottesdiener KM, Wagner
use of lopinavir/ritonavir and rifampicin. AIDS 2009, 23:863–865. JA, Iwamoto M: Effect of rifampin, a potent inducer of drug-metabolizing
73. Nijland HM, L’homme RF, Rongen GA, van Uden P, van Crevel R, Boeree MJ, enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents
Aarnoutse RE, Koopmans PP, Burger DM: High incidence of adverse events Chemother 2009, 53:2852–2856.
in healthy volunteers receiving rifampicin and adjusted doses of 90. Sauvageon H, Grinsztejn B, Arnold V, Veloso V, Vorsatz C, Pilotto JH, Grondin
lopinavir/ritonavir tablets. AIDS 2008, 22:931–935. C, Chene G, Taburet A-M, Molina J-M: Pharmacokinetics of Two Doses of Ral-
74. Murphy RA, Marconi VC, Gandhi RT, Kuritzkes DR, Sunpath H: tegravir in Combination with Rifampin in HIV-TB co-infected Patients, an ANRS
Coadministration of lopinavir/ritonavir and rifampicin in HIV and 12 180 Reflate TB sub-study [abstract 539]. Atlanta, GA: Program and abstracts
tuberculosis co-infected adults in South Africa. PLoS ONE 2012, 7:e44793. of the 20th Conference on Retroviruses and Opportunistic Infections; 2013.
75. Decloedt EH, Maartens G, Smith P, Merry C, Bango F, McIlleron H: The safety, 91. Mena A, Vazquez P, Castro A, Lopez S, Bello L, Pedreira JD: Clinical
effectiveness and concentrations of adjusted lopinavir/ritonavir in HIV-infected experience of raltegravir-containing regimens in HIV-infected patients
adults on rifampicin-based antitubercular therapy. PLoS ONE 2012, 7:e32173. during rifampicin-containing treatment of tuberculosis. J Antimicrob
76. Sant’Anna FM, Velasque L, Costa MJ, Schmaltz CA, Morgado MG, Lourenco Chemother 2011, 66:951–952.
MC, Grinsztejn B, Rolla VC: Effectiveness of highly active antiretroviral 92. Grinsztejn B, De Castro N, Arnold V, Veloso V, Pilotto JH, Brites C, Vorsatz C,
therapy (HAART) used concomitantly with rifampicin in patients with Grondin C, Chene G, Molina J-M: Efficacy and Safety of Raltegravir vs Efavirenz
tuberculosis and AIDS. Braz J Infect Dis 2009, 13:362–366. for the Treatment of HIV/TB patients: 48-week Results of the ANRS 12 180 Re-
77. Singh R, Marshall N, Smith CJ, Reynolds CJ, Breen RA, Bhagani S, Cropley I, flate TB Trial [abstract 853]. Atlanta, GA: Program and abstracts of the 20th
Hopkins S, Swaden L, Johnson MA, Lipman MC: No impact of rifamycin Conference on Retroviruses and Opportunistic Infections; 2013.
selection on tuberculosis treatment outcome in HIV coinfected patients. 93. Dooley KE, Sayre P, Borland J, Purdy E, Chen S, Song I, Peppercorn A, Everts
AIDS 2013, 27:481–484. S, Piscitelli S, Flexner C: Safety, tolerability, and pharmacokinetics of the
78. Matteelli A, Carvalho AC, Apostoli A, Tinelli C, Scudeller L, El Hamad I, HIV integrase inhibitor dolutegravir given twice daily with rifampin or
Bonora S, Girardi E, Gori A, Mussini C: Completion Rate and Viro-Immunological once daily with rifabutin: results of a phase 1 study among healthy
Response to Combined TB/HIV Treatment: Results from the RIFART Study. subjects. J Acquir Immune Defic Syndr 2013, 62:21–27.
[Abstract 854]. Atlanta, GA: Program and abstracts of the 20th Conference on 94. Lawn SD, Torok ME, Wood R: Optimum time to start antiretroviral therapy
Retroviruses and Opportunistic Infections; 2013. during HIV-associated opportunistic infections. Curr Opin Infect Dis 2011,
79. Boulanger C, Hollender E, Farrell K, Stambaugh JJ, Maasen D, Ashkin D, Symes 24:34–42.
S, Espinoza LA, Rivero RO, Graham JJ, Peloquin CA: Pharmacokinetic 95. Blanc FX, Sok T, Laureillard D, Borand L, Rekacewicz C, Nerrienet E, Madec Y,
evaluation of rifabutin in combination with lopinavir-ritonavir in patients Marcy O, Chan S, Prak N, Kim C, Lak KK, Hak C, Dim B, Sin CI, Sun S, Guillard
with HIV infection and active tuberculosis. Clin Infect Dis 2009, 49:1305–1311. B, Sar B, Vong S, Fernandez M, Fox L, Delfraissy JF, Goldfeld AE, CAMELIA
80. Khachi H, O’Connell R, Ladenheim D, Orkin C: Pharmacokinetic interactions (ANRS 1295–CIPRA KH001) Study Team: Earlier versus later start of
between rifabutin and lopinavir/ritonavir in HIV-infected patients with antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J
mycobacterial co-infection. J Antimicrob Chemother 2009, 64:871–873. Med 2011, 365:1471–1481.
96. Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, 112. Sharma SK, Singla R, Sarda P, Mohan A, Makharia G, Jayaswal A, Sreenivas V,
Gengiah T, Gengiah S, Naidoo A, Jithoo N, Nair G, El-Sadr WM, Friedland G, Singh S: Safety of 3 different reintroduction regimens of antituberculosis
Abdool Karim Q: Integration of antiretroviral therapy with tuberculosis drugs after development of antituberculosis treatment-induced hepato-
treatment. N Engl J Med 2011, 365:1492–1501. toxicity. Clin Infect Dis 2010, 50:833–839.
97. Török ME, Yen NT, Chau TT, Mai NT, Phu NH, Mai PP, Dung NT, Chau NV, 113. Schutz C, Ismail Z, Proxenos CJ, Marais S, Burton R, Kenyon C, Maartens G,
Bang ND, Tien NA, Minh NH, Hien NQ, Thai PV, Dong DT, Anh do TT, Thoa Wilkinson RJ, Meintjes G: Burden of antituberculosis and antiretroviral
NT, Hai NN, Lan NN, Lan NT, Quy HT, Dung NH, Hien TT, Chinh NT, drug-induced liver injury at a secondary hospital in South Africa.
Simmons CP, de Jong M, Wolbers M, Farrar JJ: Timing of initiation of S Afr Med J 2012, 102:506–511.
antiretroviral therapy in human immunodeficiency virus (HIV)–associated 114. Lehloenya RJ, Dheda K: Cutaneous adverse drug reactions to anti-
tuberculous meningitis. Clin Infect Dis 2011, 52:1374–1383. tuberculosis drugs: state of the art and into the future. Expert Rev Anti
98. Manosuthi W, Mankatitham W, Lueangniyomkul A, Thongyen S, Infect Ther 2012, 10:475–486.
Likanonsakul S, Suwanvattana P, Thawornwan U, Suntisuklappon B, 115. Toma E, Fournier S: Adverse reactions to co-trimoxazole in HIV infection.
Nilkamhang S, Sungkanuparph S: Time to initiate antiretroviral therapy Lancet 1991, 338:954.
between 4 weeks and 12 weeks of tuberculosis treatment in HIV- 116. Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, Naldi L, Viboud C, Roujeau
infected patients: results from the TIME study. J Acquir Immune Defic JC: Nevirapine and the risk of Stevens-Johnson syndrome or toxic epi-
Syndr 2012, 60:377–383. dermal necrolysis. AIDS 2001, 15:1843–1848.
99. Marais S, Meintjes G, Pepper DJ, Dodd LE, Schutz C, Ismail Z, Wilkinson KA, 117. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D: Incidence of
Wilkinson RJ: Frequency, severity, and prediction of tuberculous serious side effects from first-line antituberculosis drugs among patients
meningitis immune reconstitution inflammatory syndrome. Clin Infect Dis treated for active tuberculosis. Am J Respir Crit Care Med 2003, 167:1472–1477.
2013, 56:450–460. 118. Lehloenya RJ, Todd G, Badri M, Dheda K: Outcomes of reintroducing anti-
100. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, tuberculosis drugs following cutaneous adverse drug reactions. Int J
Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan Tuberc Lung Dis 2011, 15:1649–1657.
R, Sterling TR, ATS (American Thoracic Society) Hepatotoxicity of 119. Kenyon C, Wearne N, Burton R, Meintjes G: The risks of concurrent
Antituberculosis Therapy Subcommittee: An official ATS statement: treatment with tenofovir and aminoglycosides in patients with hiv-
hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006, associated tuberculosis. South Afr J HIV Med 2011, 12:43–45.
174:935–952. 120. Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W, Elliott
101. Montessori V, Press N, Harris M, Akagi L, Montaner JS: Adverse effects of JH, Murdoch D, Wilkinson RJ, Seyler C, John L, van der Loeff MS, Reiss P,
antiretroviral therapy for HIV infection. CMAJ 2004, 170:229–238. Lynen L, Janoff EN, Gilks C, Colebunders R, International Network for the
102. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, Study of HIV-associated IRIS: Tuberculosis-associated immune reconstitu-
Cahn P, Lalloo UG, van der Westhuizen IP, Malan DR, Johnson MA, Santos tion inflammatory syndrome: case definitions for use in resource-limited
BR, Mulcahy F, Wood R, Levi GC, Reboredo G, Squires K, Cassetti I, Petit D, settings. Lancet Infect Dis 2008, 8:516–523.
Raffi F, Katlama C, Murphy RL, Horban A, Dam JP, Hassink E, van Leeuwen R, 121. Lawn SD, Bekker LG, Miller RF: Immune reconstitution disease associated
Robinson P, Wit FW, Lange JM, 2NN Study team: Comparison of first-line with mycobacterial infections in HIV-infected individuals receiving antire-
antiretroviral therapy with regimens including nevirapine, efavirenz, or trovirals. Lancet Infect Dis 2005, 5:361–373.
both drugs, plus stavudine and lamivudine: a randomised open-label 122. Lawn SD, Myer L, Bekker LG, Wood R: Tuberculosis-associated immune
trial, the 2NN Study. Lancet 2004, 363:1253–1263. reconstitution disease: incidence, risk factors and impact in an
103. Lorent N, Sebatunzi O, Mukeshimana G, den EJ V, Clerinx J: Incidence and antiretroviral treatment service in South Africa. AIDS 2007, 21:335–341.
risk factors of serious adverse events during antituberculous treatment 123. Breen RA, Smith CJ, Bettinson H, Dart S, Bannister B, Johnson MA, Lipman
in Rwanda: a prospective cohort study. PLoS ONE 2011, 6:e19566. MC: Paradoxical reactions during tuberculosis treatment in patients with
104. Yimer G, Aderaye G, Amogne W, Makonnen E, Aklillu E, Lindquist L, Yamuah and without HIV co-infection. Thorax 2004, 59:704–707.
L, Feleke B, Aseffa A: Anti-tuberculosis therapy-induced hepatotoxicity 124. Burman W, Weis S, Vernon A, Khan A, Benator D, Jones B, Silva C, King B,
among Ethiopian HIV-positive and negative patients. PLoS ONE 2008, LaHart C, Mangura B, Weiner M, El-Sadr W: Frequency, severity and dur-
3:e1809. ation of immune reconstitution events in HIV-related tuberculosis.
105. Breen RA, Miller RF, Gorsuch T, Smith CJ, Schwenk A, Holmes W, Ballinger J, Int J Tuberc Lung Dis 2007, 11:1282–1289.
Swaden L, Johnson MA, Cropley I, Lipman MC: Adverse events and 125. Michailidis C, Pozniak AL, Mandalia S, Basnayake S, Nelson MR, Gazzard BG:
treatment interruption in tuberculosis patients with and without HIV Clinical characteristics of IRIS syndrome in patients with HIV and
co-infection. Thorax 2006, 61:791–794. tuberculosis. Antivir Ther 2005, 10:417–422.
106. Chaisson RE, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, 126. Naidoo K, Yende-Zuma N, Padayatchi N, Naidoo K, Jithoo N, Nair G, Bamber
Davis H, Boulos R, Quinn TC, Halsey NA: Six-month supervised intermittent S, Gengiah S, El-Sadr WM, Friedland G, Abdool Karim S: The immune
tuberculosis therapy in Haitian patients with and without HIV infection. reconstitution inflammatory syndrome after antiretroviral therapy
Am J Respir Crit Care Med 1996, 154:1034–1038. initiation in patients with tuberculosis: findings from the SAPiT trial.
107. Perriens JH, St Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, Portaels Ann Intern Med 2012, 157:313–324.
F, Willame JC, Mandala JK, Kaboto M, Ryder RW, Roscigno G, Piot P: 127. Meintjes G, Rangaka MX, Maartens G, Rebe K, Morroni C, Pepper DJ,
Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled Wilkinson KA, Wilkinson RJ: Novel relationship between tuberculosis
trial of treatment for either 6 or 12 months. N Engl J Med 1995, immune reconstitution inflammatory syndrome and antitubercular drug
332:779–784. resistance. Clin Infect Dis 2009, 48:667–676.
108. Marks DJ, Dheda K, Dawson R, Ainslie G, Miller RF: Adverse events to 128. Lawn SD, Wilkinson RJ, Lipman MC, Wood R: Immune reconstitution and
antituberculosis therapy: influence of HIV and antiretroviral drugs. “unmasking” of tuberculosis during antiretroviral therapy. Am J Respir Crit
Int J STD AIDS 2009, 20:339–345. Care Med 2008, 177:680–685.
109. Hoffmann CJ, Charalambous S, Thio CL, Martin DJ, Pemba L, Fielding KL, 129. Pepper DJ, Marais S, Maartens G, Rebe K, Morroni C, Rangaka MX, Oni T,
Churchyard GJ, Chaisson RE, Grant AD: Hepatotoxicity in an African Wilkinson RJ, Meintjes G: Neurologic manifestations of paradoxical
antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B. tuberculosis-associated immune reconstitution inflammatory syndrome:
AIDS 2007, 21:1301–1308. a case series. Clin Infect Dis 2009, 48:e96–e107.
110. Shipton LK, Wester CW, Stock S, Ndwapi N, Gaolathe T, Thior I, Avalos A, 130. Agarwal U, Kumar A, Behera D, French MA, Price P: Tuberculosis associated
Moffat HJ, Mboya JJ, Widenfelt E, Essex M, Hughes MD, Shapiro RL: Safety immune reconstitution inflammatory syndrome in patients infected with
and efficacy of nevirapine- and efavirenz-based antiretroviral treatment HIV: meningitis a potentially life threatening manifestation. AIDS Res Ther
in adults treated for TB-HIV co-infection in Botswana. Int J Tuberc Lung Dis 2012, 9:17.
2009, 13:360–366. 131. Muller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M: Immune
111. Kalyesubula R, Kagimu M, Opio KC, Kiguba R, Semitala CF, Schlech WF, reconstitution inflammatory syndrome in patients starting antiretroviral
Katabira ET: Hepatotoxicity from first line antiretroviral therapy: an therapy for HIV infection: a systematic review and meta-analysis. Lancet
experience from a resource limited setting. Afr Health Sci 2011, 11:16–23. Infect Dis 2010, 10:251–261.
132. Olalla J, Pulido F, Rubio R, Costa MA, Monsalvo R, Palenque E, Costa JR, Del 149. Coyne KM, Pozniak AL, Lamorde M, Boffito M: Pharmacology of
PA: Paradoxical responses in a cohort of HIV-1-infected patients with second-line antituberculosis drugs and potential for interactions with
mycobacterial disease. Int J Tuberc Lung Dis 2002, 6:71–75. antiretroviral agents. AIDS 2009, 23:437–446.
133. Breton G, Bourgarit A, Pavy S, Bonnet D, Martinez V, Duval X, Longuet P, 150. Brust JC, Shah NS, van der Merwe TL, Bamber S, Ning Y, Heo M, Moll AP,
Abgrall S, Simon A, Leport C: Treatment for tuberculosis-associated im- Loveday M, Lalloo UG, Friedland GH, Gandhi NR: Adverse events in an
mune reconstitution inflammatory syndrome in 34 HIV-infected patients. integrated, home-based treatment program for MDR-TB and HIV in
Int J Tuberc Lung Dis 2012, 16:1365–1370. KwaZulu-Natal, South Africa. J Acquir Immune Defic Syndr 2012.
134. Meintjes G, Wilkinson RJ, Morroni C, Pepper DJ, Rebe K, Rangaka MX, Oni T, 151. Arentz M, Pavlinac P, Kimerling ME, Horne DJ, Falzon D, Schunemann HJ,
Maartens G: Randomized placebo-controlled trial of prednisone for para- Royce S, Dheda K, Walson JL: Use of anti-retroviral therapy in tuberculosis
doxical tuberculosis-associated immune reconstitution inflammatory syn- patients on second-line anti-TB regimens: a systematic review. PLoS ONE
drome. AIDS 2010, 24:2381–2390. 2012, 7:e47370.
135. Lawn SD, Meintjes G: Pathogenesis and prevention of immune 152. Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, Rieder HL:
reconstitution disease during antiretroviral therapy. Expert Rev Anti Infect Short, highly effective, and inexpensive standardized treatment of
Ther 2011, 9:415–430. multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010,
136. Meintjes G, Schutz C: Preventing Tuberculosis-associated Immune Recon- 182:684–692.
stitution Inflammatory Syndrome in High-risk Patients: a Randomized
Placebo-controlled Trial of Prednisone (Pred-ART). [http://clinicaltrials.gov/ 10.1186/1741-7015-11-253
show/NCT01924286]. Cite this article as: Lawn et al.: Management of HIV-associated tubercu-
137. Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TT, Nguyen TC, losis in resource-limited settings: a state-of-the-art review. BMC Medicine
Nguyen QH, Nguyen TT, Nguyen NH, Nguyen TN, Nguyen NL, Nguyen HD, 2013, 11:253
Vu NT, Cao HH, Tran TH, Pham PM, Nguyen TD, Stepniewska K, White NJ,
Tran TH, Farrar JJ: Dexamethasone for the treatment of tuberculous
meningitis in adolescents and adults. N Engl J Med 2004, 351:1741–1751.
138. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C: Vitamin D: modulator of
the immune system. Curr Opin Pharmacol 2010, 10:482–496.
139. Conesa-Botella A, Meintjes G, Coussens AK, van der Plas H, Goliath R, Schutz
C, Moreno-Reyes R, Mehta M, Martineau AR, Wilkinson RJ, Colebunders R,
Wilkinson KA: Corticosteroid therapy, vitamin D status, and inflammatory
cytokine profile in the HIV-tuberculosis immune reconstitution inflamma-
tory syndrome. Clin Infect Dis 2012, 55:1004–1011.
140. Greenwood J, Steinman L, Zamvil SS: Statin therapy and autoimmune
disease: from protein prenylation to immunomodulation. Nat Rev
Immunol 2006, 6:358–370.
141. Sun HY, Singh N: Potential role of statins for the management of
immune reconstitution syndrome. Med Hypotheses 2010.
142. Sierra-Madero J, Tierney A, Rassool M, Azzoni L, Sereti I, Andrade J,
Mosqueda-Gomes L, Sanne I, Lederman M, CADRIS Study Team: Efficacy and
Safety of Maraviroc to Prevent Immune Reconstitution Inflammatory Syndrome
in High-risk Subjects Initiating ART: 24-Week Results of a Randomized, Placebo-
controlled Trial. Altanta, GA: Program and Abstracts of the 20th Conference
on Retroviruses and Opportunistic Infections; 2013.
143. Andrews JR, Shah NS, Gandhi N, Moll T, Friedland G: Multidrug-resistant
and extensively drug-resistant tuberculosis: implications for the HIV epi-
demic and antiretroviral therapy rollout in South Africa. J Infect Dis 2007,
196:S482–S490.
144. World Health Organization: Molecular line probe assays for rapid screning
of patients at risk of multidrug-resistant tuberculosis (MDR-TB). Policy
statement June 2008. [http://www.who.int/tb/features_archive/
policy_statement.pdf] 2008.
145. Kalokhe AS, Shafiq M, Lee JC, Ray SM, Wang YF, Metchock B, Anderson AM,
Nguyen ML: Multidrug-resistant tuberculosis drug susceptibility and
molecular diagnostic testing. Am J Med Sci 2013, 345:143–148.
146. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, Becerra
MC, Benedetti A, Burgos M, Centis R, Chan ED, Chiang CY, Cox H,
D'Ambrosio L, DeRiemer K, Dung NH, Enarson D, Falzon D, Flanagan K,
Flood J, Garcia-Garcia ML, Gandhi N, Granich RM, Hollm-Delgado MG, Holtz
TH, Iseman MD, Jarlsberg LG, Keshavjee S, Kim HR, Koh WJ: Multidrug resist-
ant pulmonary tuberculosis treatment regimens and patient outcomes: Submit your next manuscript to BioMed Central
an individual patient data meta-analysis of 9,153 patients. PLoS Med and take full advantage of:
2012, 9:e1001300.
147. Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, Gandhi
• Convenient online submission
NR, Galvani AP: Treatment outcomes among patients with multidrug-
resistant tuberculosis: systematic review and meta-analysis. Lancet Infect • Thorough peer review
Dis 2009, 9:153–161. • No space constraints or color ﬁgure charges
148. Isaakidis P, Varghese B, Mansoor H, Cox HS, Ladomirska J, Saranchuk P, Da
Silva E, Khan S, Paryani R, Udwadia Z, Migliori GB, Sotgiu G, Reid T: Adverse • Immediate publication on acceptance
events among HIV/MDR-TB co-infected patients receiving antiretroviral • Inclusion in PubMed, CAS, Scopus and Google Scholar
and second line anti-TB treatment in Mumbai. India. PLoS ONE 2012,
• Research which is freely available for redistribution
7:e40781.
Submit your manuscript at

www.biomedcentral.com/submit

Management of HIV-associated Tuberculosis in Resource-Limited Settings: A State-Of-The-Art Review

Uploaded by

Copyright:

Available Formats

Management of HIV-associated Tuberculosis in Resource-Limited Settings: A State-Of-The-Art Review

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Management of HIV-associated Tuberculosis in Resource-Limited Settings: A State-Of-The-Art Review

Uploaded by

Copyright:

Available Formats

Lawn et al.

BMC Medicine 2013, 11:253

Medicine for Global Health

REVIEW Open Access

Management of HIV-associated tuberculosis in

Introduction management for individual patients with HIV-associated

Table 5 Approaches to cotreatment for HIV-infected patients with rifampicin-susceptible tuberculosis

Submit your manuscript at

You might also like