Evaluation of a pro-active strategy for managing tuberculosis–HIV co-infection in a UK tertiary care setting

Abstract

Summary

Management of tuberculosis (TB)-HIV co-infection is complicated by interactions between the diseases and their therapies. We developed and evaluated a strategy to (i) treat co-infected patients in a single co-infection clinic, (ii) maximize use of first-line drugs, (iii) delay antiretroviral therapy (ART) until two months post-TB treatment except in severe immunosuppression, (iv) commence efavirenz at 600 mg daily with therapeutic drug monitoring (TDM) and (v) target treatment completion. We conducted a prospective cohort review over 5.5 years in a UK tertiary referral center where 56 HIV-positive patients treated for TB were followed-up for a median 30 months. Main outcome measures were treatment completion, adverse events, immune reconstitution inflammatory syndrome, immunological and virological parameters, and TDM for efavirenz. Treatment completion rates were 88% (49/56); four patients were lost to local follow-up and three (5.4%) died during treatment; no deaths were TB-related. Adverse events were common (55%), but caused no treatment interruptions. Standard doses (600 mg daily) of efavirenz with rifampicin achieved or exceeded therapeutic levels in 25/28 (89%). This study supports combined management for TB–HIV co-infected patients. Delaying ART to two months post-TB treatment did not seem to result in poor clinical outcomes in this well-resourced context. Although efavirenz 600 mg daily usually achieved satisfactory levels, TDM is recommended.

Keywords

HIV AIDS tuberculosis TB co-infection treatment outcomes antiretroviral therapy therapeutic drug monitoring immune reconstitution inflammatory syndrome efavirenz rifampicin

INTRODUCTION

Tuberculosis (TB) is the leading infectious killer of people living with HIV worldwide,¹ and the second most common opportunistic infection (OI) in the UK.² Incidence rates are greatest in the World Health Organization (WHO) Africa region;³ however, the UK also has a significant burden of disease. In London up to 25% of TB cases are infected with HIV.⁴ Managing patients with co-infection is complex due to bidirectional interactions. Not only does HIV infection increase the risk of developing TB, but TB infection increases the transcriptional activity of HIV-1.⁴ The pill burden, side effects, toxicities and interactions between anti tuberculous drugs and antiretroviral therapy (ART) lead to high rates of treatment discontinuation and interruption.⁵ Furthermore, paradoxical immune reconstitution inflammatory syndrome (IRIS) occurs following initiation of ART in an estimated 7–45% of patients.^6–8 To guide physicians through these complexities, collaborative policies and management guidelines exist,^1,2,9 but applying them in practice remains challenging.

One issue is that of timing ART initiation to balance the risk of HIV disease progression against the complications of early dual therapy.^5–8,10 ‘Paradoxical’ IRIS – worsening symptoms or signs in patients started on ART after an initial response to anti-tuberculous treatment – is associated with more advanced immunosuppression and rapid immune reconstitution; however, the most significant risk factor is starting ART within the first two months of TB therapy.^7,10

Three studies now provide evidence for the risk–benefit of early versus late ART. The CAMELIA study initially reported that in Cambodian patients with a median CD4 count of 25 cells/μL, starting ART at two versus eight weeks after TB treatment reduced 50-week mortality from 27% (90/329) to 18% (59/332).¹¹ Subsequently, the SAPIT study in South Africa (CD4 < 500 cells/μL) reported that postponing ART until TB treatment completion put patients at increased risk of HIV progression and mortality.¹² These findings contributed to changes in WHO advice favouring early ART in TB co-infection. More recent analysis of the SAPIT population has shown that while immediate (<4 weeks) versus 8–12 week initiation reduced mortality in patients with very low CD4 counts (<50), it did not in less immunocompromised patients (CD4 > 50).¹³ Thirdly, the multinational ‘STRIDE’ study demonstrated reduced incidence of AIDS and mortality with early (<2 weeks) versus later ART (8–12 weeks) in patients with CD4 < 50 cells/μL (15.5% versus 26.6%, P = 0.02), but not in the whole cohort (12.9% versus 16.1%, P = 0.45) or patients with CD4 > 50 cells/μL (11.5% versus 10.3% P = 0.67).¹⁴ However, early ART increased the incidence of TB–IRIS (11% versus 5%, P = 0.002), as previously described,^6,11 and was associated with an adverse trend in TB-related deaths (3.5% versus 1.7%, P = 0.18).¹⁴

Extrapolating from these studies, which have mainly been conducted in resource-limited settings with high rates of HIV-related mortality, to other settings may not be appropriate. In the USA, Centers for Disease Control and Prevention (CDC) recommends delaying ART for two weeks in patients with CD4 < 100 cells/μL⁹ and current UK guidelines recommend immediate ART if CD4 counts are <100 cells/μL, delayed ART (2 months) for CD4 100–200, and waiting until TB therapy completion if CD4 > 200 cells/μL.¹⁵

In terms of the choice of anti tuberculous medication, WHO and UK guidelines emphasize the importance of rifamycin-based regimens¹ and match those for HIV-negative patients.^15,16 Co-administration of rifampicin and protease inhibitors is relatively contraindicated (cytochrome P450-induction); hence efavirenz is recommended. Some authorities propose dose adjustment to 800 mg in patients >60 kg.^15,17,18 However, this may not be optimal for all patients;^19–23 black African patients particularly may clear efavirenz more slowly.^19,24

In view of the uncertainty surrounding optimal approaches to managing co-infection, this study aimed to evaluate the safety and efficacy of a combined treatment strategy based on five key components: (i) integration of TB–HIV management in a single clinic, (ii) use of first-line medications for TB unless resistance is detected, (iii) delayed commencement of ART until ≥2 months into TB therapy, except in the most immunosuppressed according to physician discretion, (generally those with CD4 count <50 cells/μL and/or multiple other OIs), (iv) use of efavirenz plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) as first-line ART, unless resistance exists and (v) use of standard dose efavirenz (600 mg/day) as the starting regimen with therapeutic drug monitoring (TDM) within 4–6 weeks of therapy. Evaluation assessed (i) the safety of this strategy in terms of morbidity, mortality and HIV progression, including occurrence of OIs, side effects, drug toxicity and TB–IRIS, and (ii) the efficacy in terms of TB treatment completion, ART continuation, achievement of therapeutic efavirenz levels, immunological and viral responses.

METHODS

Subjects included all patients attending a specialist TB–HIV co-infection clinic from April 2005 to December 2010 with primary inclusion criteria of HIV-seropositivity and a clinical diagnosis of TB (at any site) sufficiently robust to mandate anti-tuberculous therapy (fitting criteria for ‘culture-confirmed’ or ‘highly probable’ TB²⁵); patients with non-tuberculous mycobacterial infection were excluded. Data collection included demographics, diagnostic and therapeutic data, incidence of death, other OIs, side effects, toxicities and treatment interruptions, together with immunological and viral load monitoring.

Data were collected from clinical notes and laboratory records. Efavirenz concentrations were measured by high-performance liquid chromatography and trough levels predicted from standard algorithms.²⁶ Our criterion for ‘paradoxical IRIS’ was new or worsening clinical symptoms or radiological features following commencement of ART (without an alternative identifiable source) and for ‘unmasking IRIS’, the appearance of symptoms and signs of TB after commencement of ART. For both, any occurrence within the observation period was included. We generated this definition before publication of the International Network for the Study of HIV-associated IRIS (INSHI) consensus definition,²⁷ which constrains both paradoxical and unmasking IRIS to a three-month window. We present data using both definitions.

Patients were followed up for the duration of their clinic attendance. If patients transferred their care elsewhere, data were sought from their current care-providers. Statistical comparisons were made using chi-squared tests.

RESULTS

Subjects and demographics

Fifty-six patients met entry criteria of active TB and concurrent HIV infection during the study period. Patients largely originated from sub-Saharan Africa (48/56, 86%; compared with 44% of the clinic population, P < 0.0001, relative-risk 7.4); the remainder being from the UK (4), Eastern Europe (1), Latin America (1) and Southeast Asia (2). Age ranged from 18 to 56 (median 40) years, with a female predominance (F:M 4:3), reflecting country of origin epidemiology.²⁸ Body weights were available for 51 patients and averaged (median) 59.4 kg (interquartile range 54–71.7 kg). Median CD4 count was 108 cells/μL (range 2–1390), with 38 of 56 (68%) having CD4 counts <200 and 19 of 56 (34%) less than 50 cells/μL. Only 32 of 56 (57%) were known seropositive at TB diagnosis, of whom about half (15) were receiving ART; a further six had prior ARV exposure, leaving 35 (63%) treatment-naïve. TB often presented with a striking multiplicity of concomitant OIs (Supplementary Table S1, available online); 35 other HIV-related infections were diagnosed at presentation. Most patients (33/56, 59%) had pulmonary TB, and nine (27%) also had extrapulmonary disease. Thirteen (39%) were smear positive (any site), and 34 (61%) were culture positive with first-line drug resistance in four (2 rifampicin, 1 isoniazid, 1 rifampicin and isoniazid; Table 1).

Table 1

Indices of tuberculosis: anatomical site and smear/culture positivity

Site of disease	n	Smear + Culture +	Smear − Culture +	Smear + Culture −	First-line drug resistance
Pulmonary	24	7	8	0	1
Pulmonary + other site	9	5	1	1	2
Extra-pulmonary	23	5	7	3	1
Total	56	17	16	4	4*

*The isolate from one further subject was resistant to streptomycin

Goals of TB management

As our first goal was to optimize management by incorporating HIV/TB care into one clinic, we reviewed follow-up and outcome. With this approach, 46 (82%) subjects were still in follow-up at the final audit date with median follow-up duration of 907 days from TB diagnosis. In terms of treatment completion, 49 (88%) patients had documented completion of a full course of anti-tuberculous therapy. Three patients died during treatment and four were lost to local follow-up (LTFU), having moved to a different hospital (3) or overseas (1). One LTFU patient had treatment completion confirmed. In terms of the second goal, optimizing choice of TB therapy, 52 of 56 (93%) used a rifamycin-based regimen (rifampicin except 4 who took rifabutin due to co-treatment with a protease inhibitor (PI)). Standard quadruple therapy was used in all but eight patients due to drug resistance (3), potential drug interactions (1), pre-existing liver disease (1), problems monitoring vision (ethambutol avoided) (2) and physician choice (1).

Timing and choice of HIV treatment

When the relationship between timing of TB treatment and ART was considered (Figure 1a), more than a quarter, (15 of 56 27%), of TB cases occurred after starting ART. We considered 12 cases to represent ‘unmasking’ IRIS’, occurring within two years of ART, although only three met the new case-definition which proscribes an interval of <3 months.²⁷ Considering that during the same period 719 patients started ART in our clinic, we can estimate the first-year risk of ‘unmasking’ TB as ∼1.4 per 100 patient-years, assuming uniform follow-up. Of the 41 patients starting ART after TB treatment, 32 started ART during TB treatment, five after TB treatment, two have not yet commenced ART and two are LTFU.

Figure 1

Timing of clinical events in treatment of TB–HIV co-infection. (a) Interval from initiation of ART to anti-tuberculous therapy. Vertical line denotes concurrent initiation; figures to left indicate ART preceded TB treatment. (b) Timing of paradoxical IRIS reactions after initiation of ART. (c) Survival curve showing timing of death relative to initiation of anti-TB therapy. TB = tuberculosis; ART = antiretroviral therapy; IRIS = immune reconstitution inflammatory syndrome

Efavirenz and two NRTIs (usually ‘Truvada’ - emtricitabine/tenofovir) were prescribed for most patients (29/32, 91%); alternative regimens (nevirapine, 1; PI, 2) being chosen for previous intolerance. Of those commencing ART during TB therapy, 20/32 (63%) started ≥2 months after TB treatment (Table 2), consistent with the proposed strategy to only start earlier if evidence of severe immunosuppression. All patients starting ART within two months of TB treatment (12) had CD4 counts <100 cells/μL (8 were <50 cells/μL). Most (10/12, 83%) had multiple co-infections at the time of TB diagnosis (Table 2).

Table 2

Timing of ARV treatment in relation to TB treatment commencement and other opportunistic infections

Timing of ARV treatment relative to TB treatment	Patients	Mean interval (days)	CD4 mean (range) (cells/μL)	IRIS cases*	Timing of opportunistic infections relative to time of TB initiation of TB treatment
Timing of ARV treatment relative to TB treatment	Patients	Mean interval (days)	CD4 mean (range) (cells/μL)	IRIS cases*	Concurrent	<2 months	2 months to completion	After completion	Deaths
ARV before TB treatment	15	N/A		N/A					2
ARV after TB treatment
<60 days	12	27	30 (2–89)	3 (25%)	7	3	3	1	1
60–120 days	16	83	144 (3–814)	4 (25%)	7	2	3	1
>120 days to end of TB Rx	4	165	92 (4–151)	1 (25%)				1	1
After TB treatment completion	5	393	296 (242–349)	0	1		1	1
ARV not started	4	N/A	105 (21–239)	0				1	1

TB = tuberculosis; ARV = antiretroviral drug; IRIS = immune reconstitution inflammatory syndrome; Rx = treatment

Paradoxical IRIS

Of the 32 patients starting ART during TB treatment, eight (25%) met our criteria for IRIS (Table 3), of whom 5/28 (18%) met the revised definition of commencing ART more than two weeks after TB treatment and developing symptoms within three months.²⁹ In all cases ART was continued and symptoms resolved. However, one case was life-threatening, with a respiratory syndrome severe enough to require intensive care and ventilation. The interval between ART commencement and development of IRIS ranged between four and 112 days (median 35 days); three cases occurred in 12 patients starting ART <2 months after TB treatment and six of 20 where the interval was >2 months (P = 0.94 by chi-squared test) (Figure 1b; Table 3).

Table 3

Suspected TB-IRIS cases

TB diagnosis	CD4 count (cells/μL)	Timing of ARV relative to TB treatment (days)	Timing of symptoms relative to ARV (days)	Symptoms
Pulmonary/disseminated	9	77	93	Development of new psoas abscess
Pulmonary and lymph node	5	82	61	Fever, cough, weight loss, diarrhoea
Pulmonary and lymph node	10	114	28	Cough, worsening of radiological changes
Pulmonary and lymph node	11	6	4	Respiratory deterioration and hilar lymphadenopathy
Abdominal	2	7	30	Recrudescence of fever – C-reactive protein elevation
Meningitis	121	118	36	Increased oedema of cerebral deep white matter
Soft tissue infection (hand)	20	29	11	Increased soft tissue swelling
TB discitis, psoas abscess	100	124	112	Progressive lesions in the spine

TB = tuberculosis; ARV = antiretroviral drug; CRP = C-reactive protein

Adverse events

Medication-related side effects and toxicities were common, occurring in 31 of 56 (55%) patients, and mandating treatment alterations in six cases (11%). Although attribution was not possible for seven patients, side effects were deemed likely due to antituberculous medication in seven, ART in 12 and both in five (Supplementary Table S2, available online). For the 47 patients who took ART during TB treatment, there were no treatment interruptions due to adverse events or IRIS.

Clinical outcomes

No clinical TB treatment failures were observed. One patient with pulmonary, spinal and psoas disease relapsed after a three-year interval despite CD4 recovery to 459 cells/μL and an undetectable viral load. She made a good clinical response to further treatment.

Five deaths occurred in the cohort, three during and two after TB treatment (Table 2). One patient with multiple co-morbidities including Kaposi's sarcoma (KS), started ART three months prior to TB diagnosis; death 10 weeks later was attributed to sepsis and multiorgan failure. Two died during TB treatment from advanced lymphoma; one received early ART, the other was already on ART at TB diagnosis. Of those dying after TB therapy completion, one died from disseminated KS five months after successfully completing TB treatment with early ART initiation. The other declined ART and died six months later from Pneumocystis pneumonia. Median CD4 count was 77 (range 0–230 cell/μL).

In terms of new OIs or HIV-related events during or after TB treatment (Supplementary Table S1), one patient (CD4 34 cells/μL) developed cryptococcal meningitis and central nervous system (CNS) lymphoma before the end of TB treatment but was well at the end of the study period. Four patients developed non-severe HIV-related events during the study period (CIN 1, dermatophytosis and two cases of herpes zoster before ART commencement). There was no difference between rates of OIs or mortality between early (<2 months) versus late (>2 months) starters of ART (P = 0.75 by chi-squared test) (Figure 1).

Immunological and virological outcomes

Of the 48 patients on co-treatment, 44 had viral loads (VL) and CD4 counts available after treatment completion. In 35 of 44 (80%), the VL was undetectable. Of the other eight patients, seven had declining viral loads (<5000 copies/mL) and one who had electively stopped treatment had a poorly controlled viraemia. Immunologically, 41 of 44 (93%) had improving CD4 counts on ART, median increase, +88 cells/μL (range +2 to +516).

Rifampicin and efavirenz interactions

Forty patients commenced co-treatment with rifampicin and efavirenz, 33/40 (83%) at an evafirenz daily dose of 600 mg, and seven at 800 mg. At least one serum efavirenz level was taken from 33 patients (and repeat measurements in 13) during co-treatment (Figure 2). Most striking was the wide inter-individual range, from 580 to 15,325 ng/dL (recommended therapeutic range 1000–4000 ng/dL). Assessing 39 measurements in 28 patients receiving 600 mg efavirenz, only three subjects (11%) were subtherapeutic (one became therapeutic on repeat measurement); 19 patients (68%) had therapeutic levels and six (21%) had raised levels. (Similar results were obtained in an extended cohort [51 measurements in 36 subjects] where only 3 subjects were consistently subtherapeutic [Supplementary Figure S1, available online].) None of the three patients with subtherapeutic levels developed subsequent virological failure or efavirenz resistance, although two were subsequently switched to 800 mg. Of the seven patients started on efavirenz 800 mg daily, four had high efavirenz levels (>4000 ng/mL) and their dose was lowered. Of patients receiving efavirenz, 16 of 40 (40%) complained of side effects, mostly CNS-related (14), although pruritus (n = 1) and Stevens–Johnson syndrome (n = 1) also arose. Efavirenz levels correlated poorly with side effects, being >4000 ng/mL in only three of 15 of these cases (Figure 2).

Figure 2

Efavirenz levels in patients also receiving rifampicin. Predicted trough efavirenz levels (ng/dL, log scale) in patients receiving rifampicin therapy by daily dose: diamond, 400 mg; circles, 600 mg; triangles, 800 mg. Dotted line denotes minimum therapeutic level (1000 ng/dL); dashed line represents level associated with increased risk of toxicity (4000 ng/dL). Each symbol represents a single measurement in an individual patient. Data are ranked by value; where patients had more than one measurement the higher value was used for ranking assuming incomplete adherence, rather than under-dosing, was responsible for the lower value

DISCUSSION

Management of TB–HIV co-infection can be successfully integrated into a single care pathway within a single clinic setting. This is appropriate because TB co-infected patients tend to have advanced HIV disease (in this cohort most had CD4 < 200 cells/μL) with multiple concomitant HIV-related complications. Managing co-treatment within one clinic appears to result in good outcomes. Although this was not a comparative study and numbers were too small for definitive comparisons, co-infection clinics in other settings appear to improve outcomes.³⁰ As in previous studies, TB often occurred after ART initiation. It is not clear which of these cases represented ‘unmasking’ IRIS and which were incidental ART-associated TB. However, the fact that most cases occurred after the subsequently published (<3 months) provisional case-definition²⁹ suggests that this definition does not capture all relevant occurrences. The frequency of TB occurring post-ART in this population (0.6/100 person years) indicates that targeted pre-ART TB screening may be beneficial.

We observed paradoxical IRIS reactions in 28% of patients, similar to other studies in high-income countries (17–43% in France, UK and USA).^8,31–35 The frequency of IRIS, despite a deliberate strategy of delaying ART until after two months of TB treatment for most patients, underlines the importance of physician awareness. Although we had no proven deaths from such reactions, one patient became critically ill. The number of IRIS events in patients starting early versus late in this study are too small for comment (3/12 versus 6/20; P = NS), but it is recognized that IRIS and other complications are more common in patients commencing ART within two months of TB treatment and those with advanced immunosuppression.^7,14,36

Treatment side effects occurred in over half of the cohort; despite this, rates of treatment change (11%) or interruption (0) were minimized and have improved since earlier studies with more limited ART options, when a third of patients interrupted or changed treatment.⁵ Staggering treatment for patients who were not severely immunosuppressed may have contributed to this improvement and to high rates of first-line TB and HIV drug use (89% and 81%, respectively). Furthermore, this strategy did not appear to be associated with poorer outcomes, in keeping with the latest trial data from resource-limited settings;^11,13,14 80% of our patients achieved total virological control and 93% immunological improvement by completion date; only one patient in this cohort developed a clinically significant new OI during TB therapy. Good outcomes were also observed in five patients with CD4 counts <50, but who also started ART after two months of TB treatment on physician discretion. Although too small a study from which to draw conclusions, our data indicate that more research, such as a meta-analysis of completed trials, is warranted to investigate the most appropriate CD4 threshold for early initiation of ART.

With regard to efavirenz dosing, our data confirms previous findings of very wide inter-individual variability in plasma levels, poor correlation with symptoms of CNS toxicity^17,19–21 and no correlation with body weight. Our data support the use of standard doses (600 mg daily), which achieved therapeutic levels in most of this predominantly black-African cohort with an average body weight of 59 kg. Use of TDM is recommended to identify patients with low efavirenz levels, for whom a dose increase may avoid the potential for subtherapeutic levels to compromise virological control.

As in all studies performed in a specific setting, issues of generalizability and applicability arise, especially in terms of available resources for investigations such as TDM. In addition, although the study period was over 5.5 years, the patient cohort is small. Balanced against this is the risk of extrapolating from large pivotal studies in resource-limited countries with high HIV death rates to settings where the risks and benefits and availability of therapeutic options are different. Further research would benefit from prospective, multicentre studies incorporating a greater variety of patient characteristics and settings.

Combined treatment strategies for TB–HIV co-infection must target process goals (adherence to first-line therapies; low treatment interruption rates and therapeutic drug levels) in order to achieve good outcome goals (low failure rates; virological control and immunological recovery) while minimizing adverse events. Our cohort data demonstrate that co-infected patients can largely be treated with first-line medications but that a ‘one-size-fits-all’ approach, particularly regarding efavirenz dosing, is not optimal. The balance-point between the increased risks of adverse events with early ART and the risk of further HIV-related complications with delayed treatment depends upon the clinical setting.

Footnotes

ACKNOWLEDGEMENTS

We are grateful to Solene Aoutin for help with data retrieval.

Conflict of interest: none declared.

References

Getahun

Gorkom

Harries

Interim Policy on Collaborative TB/HIV Activities. Geneva: World Health Organization, 2004

Pozniak

Miller

Lipman

BHIVA treatment guidelines for tuberculosis (TB)/HIV infection 2005. HIV Med 2005;6(Suppl. 2):62–83

Corbett

Watt

Walker

The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009–21

Toossi

Mayanja-Kizza

Hirsch

Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients. Clin Exp Immunol 2001;123:233–8

Dean

Edwards

Ives

Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002;16:75–83

Lawn

Myer

Bekker

Wood

. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007;21:335–41

Murdoch

Venter

Van

Feldman

. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther 2007;4:9

Narita

Ashkin

Hollender

Pitchenik

. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158:157–61

Kaplan

Benson

Holmes

Brooks

Pau

Mansur

. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. MMWR 2009;58:1–198

10.

Lawn

Myer

Bekker

Wood

. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control. AIDS 2006;20:1605–12

11.

Blanc

Sok

Laureillard

Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365:1471–81

12.

Abdool Karim

Naidoo

Grobler

Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;362:697–706

13.

Abdool Karim

Naidoo

Grobler

Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365:1492–501

14.

Havlir

Kendall

Ive

Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365:1482–91

15.

Pozniak

Coyne

Miller

British HIV Association guidelines for the treatment of TB/HIV coinfection 2011. HIV Med 2011;12:517–24

16.

National Institute for Health and Clinical Excellence. Tuberculosis. Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London: National Institute for Health and Clinical Excellence, 2011

17.

Matteelli

Regazzi

Villani

Multiple-dose pharmacokinetics of efavirenz with and without the use of rifampicin in HIV-positive patients. Curr HIV Res 2007;5:349–53

18.

Lopez-Cortes

Ruiz-Valderas

Viciana

Pharmacokinetic interactions between efavirenz and rifampicin in HIV-infected patients with tuberculosis. Clin Pharmacokinet 2002;41:681–90

19.

Brennan-Benson

Lyus

Harrison

Pakianathan

Macallan

. Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one size does not fit all. AIDS 2005;19:1541–3

20.

Manosuthi

Sungkanuparph

Thakkinstian

Efavirenz levels and 24-week efficacy in HIV-infected patients with tuberculosis receiving highly active antiretroviral therapy and rifampicin. AIDS 2005;19:1481–6

21.

Pedral-Sampaio

Alves

Netto

Brites

Oliveira

Badaro

. Efficacy and safety of Efavirenz in HIV patients on Rifampin for tuberculosis. Braz J Infect Dis 2004;8:211–6

22.

van

Gras

Richter

Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations. J Acquir Immune Defic Syndr 2009;52:240–5

23.

van

Bannister

Mocroft

Absence of a relation between efavirenz plasma concentrations and toxicity-driven efavirenz discontinuations in the EuroSIDA study. Antivir Ther 2009;14:75–83

24.

Haas

Ribaudo

Kim

Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004;18:2391–400

25.

Dosanjh

Hinks

Innes

Improved diagnostic evaluation of suspected tuberculosis. Ann Intern Med 2008;148:325–36

26.

Jamshidi

Moreton

McKeown

Tribal ethnicity and CYP2B6 genetics in Ugandan and Zimbabwean populations in the UK: implications for efavirenz dosing in HIV infection. J Antimicrob Chemother 2010;65:2614–9

27.

Meintjes

Lawn

Scano

Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8:516–23

28.

Asimwe-Okirok

Kufa

Ntabangana

Alisalad

Calleja

JMC

. HIV/AIDS Epidemiological Surveillance Report for the WHO African Region. 2007 Update. Geneva: World Health Organization, 2007

29.

Meintjes

Wilkinson

Morroni

Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010;24:2381–90

30.

Hermans

van

Manabe

Hoepelman

Lange

Kambugu

. Earlier initiation of antiretroviral therapy, increased tuberculosis case finding and reduced mortality in a setting of improved HIV care: a retrospective cohort study. HIV Med 2012;13:337–44

31.

Breen

Smith

Bettinson

Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004;59:704–7

32.

Breton

Duval

Estellat

Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004;39:1709–12

33.

Burman

Weis

Vernon

Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis. Int J Tuberc Lung Dis 2007;11:1282–9

34.

Shelburne

Visnegarwala

Darcourt

Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005;19:399–406

35.

Cohen

Meintjes

. Management of individuals requiring antiretroviral therapy and TB treatment. Curr Opin HIV AIDS 2010;5:61–9

36.

Lawn

Bekker

Miller

. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361–73

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