Skip Navigation LinksHome > July 2009 - Volume 4 - Issue 4 > Epidemiology of HIV-associated tuberculosis
Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e32832c7d61
Epidemiology: Edited by Tim Mastro and Quarraisha Abdool-Karim

Epidemiology of HIV-associated tuberculosis

Lawn, Stephen Da,b; Churchyard, Gavinb,c,d

Free Access
Article Outline
Collapse Box

Author Information

aThe Desmond Tutu HIV Centre, Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

bDepartment of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

cAurum Institute for Health Research, Johannesburg, South Africa

dNelson R. Mandela School of Medicine, University of Kwazulu Natal, Durban, South Africa

Correspondence to Stephen D. Lawn, Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa Tel: +27 21 650 6957; fax: +27 21 650 6963; e-mail: stevelawn@yahoo.co.uk

Collapse Box

Abstract

Purpose of review: We review literature concerning the epidemiology of HIV-associated tuberculosis (HIV-TB), focusing on articles published between 2007 and 2008.

Recent findings: An estimated 1.37 million new cases of HIV-TB occurred in 2007, representing 15% of the total global burden of TB. In addition, an estimated 456 000 HIV-TB deaths accounted for 23% of global HIV/AIDS mortality. Sub-Saharan Africa is the worst affected region with 79% of the disease burden. The epicentre of the coepidemic lies in the south of the continent, with South Africa alone accounting for over one quarter of all cases. A critical overlap between HIV and the global multidrug-resistant TB epidemics is emerging. Although it is as yet unclear whether HIV is driving a disproportionate increase in multidrug-resistant TB cases at a population level, HIV has nevertheless been a potent risk factor for institutional outbreaks, especially in South Africa and eastern Europe. Increasing data have highlighted the risk of TB among HIV-infected healthcare workers in resource-limited settings. However, many studies also show the major benefits to be derived from antiretroviral therapy in high-income and low-income countries.

Summary: HIV-TB remains a major challenge to global health that requires substantial increases in resource allocation and concerted international action.

Back to Top | Article Outline

Introduction

From the early stages of the HIV epidemic, a strong association with tuberculosis (TB) was apparent [1] and HIV subsequently emerged as one of the key factors undermining global TB control [2]. The epicentre of this coepidemic is in southern Africa, where TB incidence rates have risen to unprecedented levels [3••]. The situation has been further compounded by the intersection with the growing global epidemic of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (and XDR-TB), especially in eastern Europe and South Africa. In this paper, we review the current global disease burden, recent epidemiological studies that provide insights into the epidemic and the impact of the increasing availability of antiretroviral therapy (ART) in both high-resource and low-resource settings.

Back to Top | Article Outline

Global burden of HIV-associated tuberculosis

Between 1990 and 2003, HIV infection was one of the key factors underlying an approximately 1% annual increase in the global TB incidence. World Health Organization (WHO) estimates that global TB incidence peaked at 142 cases per 100 000 population in 2004 and that it is now decreasing slowly [3••]. However, as a result of global population growth, the absolute number of TB cases globally continued to rise in 2007. Trends in recent years also suggest that the annual number of incident cases of HIV-associated TB (HIV-TB) peaked at 1.39 million cases in 2005 and is now decreasing [3••].

In 2007, there were an estimated 9.3 million new cases of TB worldwide. Among these, there were 1.37 million (14.8%) cases of HIV-TB and approximately 456 000 HIV-TB deaths [3••]. Sub-Saharan Africa accounted for the vast majority (79%) of cases, with the coepidemic being particularly concentrated in the countries of southern Africa where HIV prevalence is highest (Figs 1 and 2). The south-east Asian region accounted for 11% of cases [3••].

Figure 1
Figure 1
Image Tools
Figure 2
Figure 2
Image Tools

These estimates released by WHO in 2009 represent a substantial increase from previous estimates, with an approximately two-fold greater disease burden [3••,4•]. These new estimates have arisen because of the substantial increase in HIV-testing among TB patients, particularly in Africa where the proportion of TB patients being tested for HIV has increased greatly in recent years, reaching 37% of TB patients in 2007 [3••]. Thus, much more reliable data on the prevalence of HIV in TB patients are now available. Using these data, the relative risk of HIV-infected people developing TB compared with HIV-negative people has been revised. Previously, this ratio was estimated to be approximately 6 in populations with a generalized HIV epidemic but has now been revised to 20.6 [95% confidence interval (CI) 20.4–34.9] [3••,4•]. These revised estimates indicate that the scale of the challenge of HIV-TB is considerably greater than previously thought.

Regional trends in the overall rate of HIV-TB are uncertain at present. However, overall, TB notification rates in many countries in southern Africa had started to decrease between 2003 and 2006 (Fig. 3) [4•]. These trends are perhaps most likely to reflect the natural evolution of the HIV epidemic; the contribution, if any, of other potential factors such as scale-up of ART are as yet unknown. South Africa and Swaziland are the exception to this trend, with rates continuing to rise in 2007 and this may reflect the later development of the HIV epidemic in these countries [3••]. With just 0.7% of the world's population, South Africa accounted for 28% of the global burden of HIV-associated TB in 2006 (Fig. 2) [4•].

Figure 3
Figure 3
Image Tools

HIV-TB is also an important public health challenge in eastern Europe. Here, the overlap of the HIV and anti-TB drug resistance epidemics is an important factor in the rising TB rates observed in the region (Fig. 3). A study of 25 of the highest burden countries in the WHO European region found that the proportion of TB cases testing positive increased from 2.1% in 2004 to 3.3% in 2005, with Ukraine accounting for much of this [5•]. The highest incidence rates of HIV-TB were in Portugal, followed by Ukraine, Estonia, the Russian Federation and Latvia. England and Wales were not included in this study but here HIV prevalence among TB cases has increased from 3.1% in 1999 to 8.3% in 2003 [6•]. HIV-coinfected cases contributed almost one third to the increase in overall TB notifications in England and Wales in this period and the majority were non-UK born. In marked contrast, the United States experienced a three-fold decrease in the number of HIV-TB cases between 1993 and 2004, coinciding with improvements in TB control and advances in HIV diagnosis and treatment [7].

Back to Top | Article Outline

HIV-associated tuberculosis and mortality

Patients with HIV-TB have high mortality risk [8–13] and TB is a leading cause of death in HIV-infected patients in TB endemic countries, including those with free access to ART such as in Brazil [14•]. TB is also associated with an increased risk of AIDS-related deaths in men and women living in the United States [15•,16]. WHO estimates that there were a total of 456 000 HIV-TB deaths in 2007 [3••]. This number equates to 33% of the number of incident HIV-TB cases that year. Moreover, this represents 23% of the estimated 2 million deaths from HIV/AIDS in 2007. Such deaths are routinely classified as ‘HIV deaths’ rather than ‘TB deaths’ in the International Statistical Classification of Diseases (ICD-10).

Deaths from HIV-TB have exacted a huge toll on the worst affected communities in sub-Saharan Africa. In a rural South African community with high HIV prevalence, there has been an increasing trend in TB mortality since 1994 in HIV-infected but not HIV-uninfected TB patients, especially in young adults [12]. In recent years, the excess HIV-TB mortality has been 1.6-fold greater in women compared with men. Observed regional differences in death rates in Ugandan and Malawian patients with HIV-TB are likely be due to differences in patient age and stage of HIV epidemic [9].

Consistent with previous randomized clinical trials, cotrimoxazole prophylaxis significantly reduced mortality risk in HIV-infected pulmonary TB patients in Zambia [8]. Together with post-mortem data from South Africa [17•], these data highlight bacterial sepsis as a likely frequent cause of death in these patients.

Back to Top | Article Outline

HIV and recurrent tuberculosis

A systematic review of 32 studies [18] and recently published data from Rio de Janeiro, South African gold mines and San Francisco [19••,20•,21•] confirm that HIV-TB patients are at increased risk of recurrent disease, especially those with low CD4 cell counts. Consistent with an earlier study [22], molecular epidemiological data from South African gold mines [20•] suggest that exogenous reinfection accounts for approximately two-thirds of recurrent disease. This contrasts with data from the low-TB burden setting of San Francisco where the relapse rate among HIV-infected patients was substantially reduced by increased duration of TB treatment, suggesting the importance of relapse in this setting [18]. Increased duration of TB treatment, use of antiretroviral treatment and secondary isoniazid prophylaxis are all strategies that may reduce recurrence rates [19••,21•,23].

Back to Top | Article Outline

Epidemiological studies in sub-Saharan Africa

The WHO DOTS strategy has proven insufficient to control TB in high HIV prevalence communities in southern Africa [24]. Adjunctive interventions are needed but must be based upon sound epidemiological data derived from community-based studies.

A study of an HIV-seroconverter cohort of gold miners found that TB risk did not increase during the HIV seroconversion period but that TB risk rapidly increased three-fold within the first 2 years of HIV infection. Thereafter, TB incidence increased steadily with time such that by 11 years from seroconversion, nearly half the HIV-infected men had developed TB [25••].

In a township in Cape Town, South Africa, the annual TB notification rate reached 1500/100 000 in 2004 [24] and exceeded 2000/100 000 in 2006 [26••]. This rate is almost unprecedented in era of multidrug TB treatment and has been driven by high HIV prevalence in the context of poverty and overcrowding [24]. Despite a reasonably well functioning DOTS service in this community achieving a 67% case-finding rate in HIV-uninfected adults, a cross-sectional survey found a very high prevalence of undiagnosed TB (5%) among HIV-infected people and a case-finding proportion of just 37% [27•]. TB disease duration (and period of infectiousness) in the community was similar among HIV-infected and uninfected individuals, contrasting with earlier studies from South African gold miners and Zimbabwean factory workers in which disease duration was substantially shorter in HIV-infected people [28,29••]. Various factors may underlie this difference, including health-seeking behaviour, access to care, efficiency of TB treatment services and stage of evolution of the HIV epidemic. Studies from Cape Town and Harare, however, agree that a significant proportion of patients with culture-positive TB identified through active screening have subclinical disease [27•,29••].

The high prevalence of undiagnosed TB is the key driver of transmission in these communities. The annual risk of infection among school children in a poor community in Cape Town was found to be approximately 4–5% [26••]. As a result, approximately 50% were infected by the age of 15 years and were thus primed for development of TB in the event of subsequent HIV acquisition in early adult life. Among adults in South African townships and gold mines, the prevalence of TB infection is 77–89% [30–32]. Enhanced case finding such as that described in a work place intervention in Harare, Zimbabwe [29••] may be a key intervention to reduce high transmission rates.

HIV-TB is generally less infectious and the impact of this disease burden on overall transmission in high-burden communities is not clear. Consistent with previous data, the study by Middelkoop et al. [26••] provides no evidence that the HIV-TB epidemic has resulted in increased TB transmission to children, which largely occurs in the home. However, in some settings within communities, a large number of HIV-TB cases may outweigh any effect of reduced infectiousness and result in increased transmission among adults. For example, Glynn et al. [25••] suggested that increased secondary transmission accounted for rising TB rates in both HIV-infected and noninfected workers in a South African gold mine, which contrasts with an earlier study [33]. Collectively, these data suggest that the contribution of HIV-TB to transmission is variable and may be age-specific.

Back to Top | Article Outline

HIV and multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis epidemics

Approximately 425 000 MDR-TB cases occur annually worldwide, representing nearly 5% of the world's annual TB burden [34]. The interrelationship between the MDR-TB and HIV epidemics has been comprehensively reviewed elsewhere [35••]. By fuelling increased TB incidence rates, HIV may also be contributing to increases in absolute numbers of MDR-TB cases. However, the evidence to support a disproportionate association between the two diseases at a population level has not been conclusive [35••]. Nevertheless, a more recent study from the Ukraine (where the rates of MDR-TB are among the highest in the world) found a significant independent association between HIV and MDR-TB (adjusted odds 1.7, 95% CI 1.3–2.3) [36•]. It is also notable that more than half of the XDR-TB patients reported in the United States between 1993 and 2007 were HIV-infected [37].

HIV infection is associated with institutional outbreaks of MDR-TB as first described in industrialized countries in the late 1980s and early 1990s [35••]. The risk associated with newly expanding HIV care and treatment services in resource-limited settings was vividly exemplified by the Tugela Ferry hospital outbreak in rural Kwazulu Natal in South Africa in 2005 and 2006 [38]. Surveillance during this outbreak found that 39% of patients had MDR-TB and 6% had XDR-TB. Of those with XDR-TB, only half had previously received TB treatment, two-thirds had a recent hospital admission and genotyping found that 85% of strains were similar. All those tested were HIV-infected [38] and 52 of 53 patients died with median survival of 16 days from diagnosis; two deaths were among healthcare workers.

Further molecular epidemiological studies of patients with more than one TB episode confirm that exogenous reinfection was frequently the source of drug-resistant disease at this hospital in Kwazulu Natal [39•]. The causal strain has been identified as F15/LAM4/KZN and this has been associated with MDR-TB in the province as early as 1994 and with XDR-TB from 2001 [40•]. The lack of drug susceptibility testing and drug resistance surveillance permitted the evolution of the XDR-TB strain to go undetected until the Tugela Ferry outbreak.

The Tugela Ferry outbreak developed in the context of a very poorly functioning provincial TB control programme. Moreover, there was a critical lack of TB infection control measures within this health facility where the prevalence of both HIV and TB were high [41]. Evidence is growing that this was not a sporadic localized outbreak. Cases have been identified in patients attending approximately 60 different health facilities in Kwazulu Natal Province and in all nine provinces of South Africa [42]. Such outbreaks threaten to overwhelm public health programmes and undermine the successes of ART. However, the extent to which HIV-associated MDR-TB and XDR-TB will lead to a rise in drug-resistant TB in the general community remains to be determined.

Back to Top | Article Outline

Nosocomial tuberculosis transmission and infection control

Studies of the infectiousness of hospital in-patients with HIV-TB have been conducted in Peru using an air sampling system that exposed guinea pigs to exhaust air within an animal facility above the ward [43,44••]. These studies found that the infectiousness of patients receiving treatment varied greatly and that a small number of inadequately treated HIV patients with MDR-TB were responsible for almost all transmission events [43,44••]. Patients enrolling in ART clinics in resource-limited settings have a high prevalence of untreated TB [45,46]. Patients with sputum smear-positive disease are most infectious and yet represent a minority of the disease burden and can be rapidly diagnosed by sputum examination. In contrast, there are often substantial delays in diagnosis among the large number of those with smear-negative culture-positive pulmonary TB and such patients are a potentially important source of nosocomial transmission [47].

The risk of TB among healthcare workers in low-income and middle-income countries is an increasingly recognized problem [48]. In Zimbabwe, nursing students had an extremely high risk of acquiring TB infection (19.3/100 person-years) [49•]. In a systematic review, the median annual incidence of TB infection attributable to healthcare work in low-resource settings was 5.8% compared with 1.1% in high-income countries [50]. This has major implications for countries where a significant proportion of healthcare workers are HIV-infected. In Kenya, for example, HIV-infected healthcare workers were found to have a much higher risk of developing TB (adjusted odds 29.1; 95% CI 5.1–167) [51••].

TB infection control in health facilities in resource-limited settings has been hugely neglected, but in the era of rapid expansion of HIV care and treatment services and increasing MDR-TB prevalence, this is increasingly recognized as a high priority [52•]. Simple low-cost interventions such as increased natural ventilation, upper-room ultraviolet lights and negative air ionization may be very effective [53•,54••]. An epidemiological modelling study based on the Tugela Ferry outbreak of XDR-TB suggested that if no TB infection control measures were instituted, about 1300 cases of XDR-TB would occur by the end of 2012 [55••]. However, implementation of a combination of administrative, environmental and personal infection control measures was estimated to nearly halve this number of cases.

Back to Top | Article Outline

Tuberculosis and antiretroviral therapy

In recent years, access to ART has been rapidly scaled up in resource-limited settings where the burden of TB is highest. Increasing data from around the world indicate the substantial impact that ART has on HIV-TB.

Back to Top | Article Outline
Impact of antiretroviral therapy on survival of tuberculosis/HIV patients

The apparent complexity of concurrent administration of ART during TB treatment may have resulted in either the underutilization or delayed initiation of this key intervention. However, increasing data indicate the huge survival benefit of ART for patients with HIV-associated TB. In the Netherlands, there has been a 54% reduction in the adjusted odds of death among those with HIV-TB during the ART era [10]. In Thailand [56,57] and Spain [58], adjusted mortality risk is estimated to be reduced by 80–93% and 63%, respectively. In Malawi, adults and children with TB receiving ART have good outcomes similar to non-TB patients [59,60]. Surprisingly, a further retrospective observational study from Malawi found no short-term survival benefit conferred by ART started during the continuation phase of TB treatment but this study may well be subject to ART allocation bias [61]. Furthermore, most deaths occurred in the intensive phase of TB treatment [61], suggesting the need for early ART initiation [62]. Consistent with data from South Africa [45], patients developing incident TB during ART in Malawi have much poorer survival [63]. This reflects the fact that TB develops opportunistically in those patients with poor CD4 cell recovery and who already have poor survival [64].

Back to Top | Article Outline
Tuberculosis and mortality in antiretroviral therapy services

TB is a leading cause of early mortality in ART services in sub-Saharan Africa [65], although much of the true burden of disease may remain unascertained. In an ART service in South Africa, TB was associated with a two to three-fold increased crude mortality risk [45]. However, some data from ART services in Uganda, Malawi and South Africa suggest that TB is not an independent predictor of mortality, which instead appears to be largely driven by low baseline CD4 cell counts [46,66,67]. As patients with HIV-TB typically have advanced immunodeficiency and very high morality risk, early initiation of ART is often warranted [62]. The precise timing of this remains unclear and randomized controlled trials are awaited [68].

Back to Top | Article Outline
Impact of antiretroviral therapy on tuberculosis prevention

The WHO DOTS strategy alone is insufficient to control the HIV-TB epidemic. ART, however, is a potent intervention for TB prevention. Adding to earlier data [69], recent studies have shown a 54–74% reduction in TB rates associated with use of ART in an adult cohort in Spain [70,71] and at a population level in Brazil [72••,73]. Recurrence rates were halved by ART in a study from Brazil [19••]. Furthermore, in a retrospective hospital-based paediatric cohort in South Africa, the extremely high TB incidence rates (53.3 cases/100 person-years) decreased by 88% during ART [74•].

TB incidence rates decline with increasing duration of ART [45,46] and risk reductions observed in cohorts in high-income and low-income countries are similar [75•]. Despite this, it remains unclear whether ART will improve TB control at the population level [69,76]. A study from Brazil found that much HIV-TB occurs prior to HIV diagnosis [77] and early HIV diagnosis and treatment are clearly needed for TB prevention. In addition, as TB rates do not return to background during ART [45], concurrent adjunctive interventions are needed. Isoniazid preventive therapy in a routine clinical service reduces the risk of HIV-TB substantially [78]. More recent retrospective observational data from Brazil suggest that isoniazid preventive therapy and ART used together may have an additive effect [72••]. Concurrent use of these treatments was not associated with an increased risk of hepatitis in South African gold miners [79]. In eastern Europe where rates of HIV-associated drug-resistant disease are high, a system dynamics simulation model suggested that very high coverage (>75%) with ART combined with high TB treatment success rates would need to be achieved to substantially impact mortality rates associated with TB [80].

Back to Top | Article Outline
Tuberculosis-associated immune reconstitution disease

The early phase of ART may be complicated by the development of immune reconstitution disease (IRD), alternatively known as immune reconstitution inflammatory syndrome (IRIS). Although this is associated with a wide variety of opportunistic infections, mycobacterial diseases are the most common [81]. TB accounted for 41% of IRD events in a prospective South African cohort [82•].

TB IRD was reviewed in 2008 [83•] and may present as either the clinical deterioration of preexisting TB following ART initiation (paradoxical IRD) or the clinical presentation of subclinical TB present at the time of ART initiation (unmasking TB). Between 8 and 43% of TB patients who commence ART develop paradoxical IRD, with a tendency for lower rates to be observed in studies in resource-limited settings [83•]. The reasons for this apparent difference are not clear but recently published consensus case definitions may help standardization of data [84•].

Although just 12% of TB patients developed IRD in a study from South Africa, the proportion was much higher (32%) among the subset who initiated ART in the first 2 months of TB treatment [85••]. In adjusted analyses, those initiating ART in the first month of TB treatment had a 70-fold higher risk of TB IRD compared with those initiating ART after at least 3 months of TB treatment. A further prospective study from the United States found a rate of just 15% but highlighted the considerable morbidity and frequent need for interventions [86].

For a long time ‘unmasking’ TB IRD has remained a poorly defined phenomenon but has recently been extensively reviewed [87•,88]. Both papers provide a similar conceptual framework that proposes how ART modifies the presentation of TB. This may cause a temporal clustering of cases in the initial weeks of treatment – a phenomenon referred to as ‘unmasking’. In a subset of these cases, there may also be an increase in the severity of manifestations due to an overt hyperinflammatory response – a phenomenon referred to as ‘unmasking TB IRD’ [87•,88]. Although reports of the latter in the literature are relatively few, a recent case report illustrates how this is occasionally fatal [89].

Back to Top | Article Outline

Conclusion

HIV-TB accounts for a huge burden of morbidity and mortality, which, in light of revised WHO estimates in 2009 [3••], has previously been underestimated. The African continent bears the brunt of the vast majority of this disease burden and associated mortality. However, rates are also increasing in some middle-income and high-income countries.

Although much needs to be done to improve diagnosis and treatment outcomes, it is also clear that this epidemic cannot be controlled solely through treatment of infectious TB cases. There is a great need for scale-up of preventive interventions [90•] such as the WHO ‘3I's strategy’ (intensified case finding, isoniazid preventive therapy and infection control) and ART. In addition, a much stronger focus on prevention needs to include concerted action with regard to HIV/AIDS prevention and addressing social determinants of disease such as poverty, malnutrition and overcrowding [90•]. To accelerate progress towards epidemiological impact targets set for 2015, HIV-TB must move up the global public health agenda with increased resource allocation and concerted international action.

Back to Top | Article Outline

Acknowledgements

S.D.L. is funded by the Wellcome Trust, London, UK. G.C. is partly funded by the Consortium to Respond Effectively to the AIDS and Tuberculosis Epidemics (CREATE).

The authors have no conflicts of interest.

Back to Top | Article Outline

References and recommended reading

Back to Top | Article Outline

Papers of particular interest, published within the annual period of review, have been highlighted as:

Back to Top | Article Outline

• of special interest

Back to Top | Article Outline

•• of outstanding interest

Back to Top | Article Outline

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 341–342).

1 Rieder HL, Cauthen GM, Comstock GW, Snider DE Jr. Epidemiology of tuberculosis in the United States. Epidemiol Rev 1989; 11:79–98.

2 Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163:1009–1021.

3•• World Health Organization. Global tuberculosis control. Epidemiology, strategy, financing. Geneva: World Health Organization; 2009. WHO/HTM/TB/2009.411. A comprehensive overview of the burden of TB at global, regional and national levels with data available up to 2007. In this report, increasing availability of data has permitted the estimates of the burden of HIV-TB to be revised. New estimates of the annual number of cases occurring worldwide are almost double the number previously estimated.

4• World Health Organization. Global tuberculosis control. Surveillance, planning and financing. Geneva: World Health Organization; 2008. WHO/HTM/TB/2008.393. A comprehensive annual overview of the burden of TB at the global, regional and national levels using data available up to 2006.

5• Lazarus JV, Olsen M, Ditiu L, Matic S. Tuberculosis-HIV co-infection: policy and epidemiology in 25 countries in the WHO European region. HIV Med 2008; 9:406–414.

6• Ahmed AB, Abubakar I, Delpech V, et al. The growing impact of HIV infection on the epidemiology of tuberculosis in England and Wales: 1999 2003. Thorax 2007; 62:672–676.

7 Albalak R, O'Brien RJ, Kammerer JS, et al. Trends in tuberculosis/human immunodeficiency virus comorbidity, United States, 1993–2004. Arch Intern Med 2007; 167:2443–2452.

8 Nunn AJ, Mwaba P, Chintu C, et al. Role of co-trimoxazole prophylaxis in reducing mortality in HIV infected adults being treated for tuberculosis: randomised clinical trial. BMJ 2008; 337:a257.

9 Ciglenecki I, Glynn JR, Mwinga A, et al. Population differences in death rates in HIV-positive patients with tuberculosis. Int J Tuberc Lung Dis 2007; 11:1121–1128.

10 Haar CH, Cobelens FG, Kalisvaart NA, et al. HIV-related mortality among tuberculosis patients in The Netherlands, 1993–2001. Int J Tuberc Lung Dis 2007; 11:1038–1041.

11 Cain KP, Kanara N, Laserson KF, et al. The epidemiology of HIV-associated tuberculosis in rural Cambodia. Int J Tuberc Lung Dis 2007; 11:1008–1013.

12 Zwang J, Garenne M, Kahn K, et al. Trends in mortality from pulmonary tuberculosis and HIV/AIDS co-infection in rural South Africa (Agincourt). Trans R Soc Trop Med Hyg 2007; 101:893–898.

13 Duarte EC, Bierrenbach AL, Barbosa da Silva JJ, et al. Associated factors with deaths among pulmonary tuberculosis patients: a case–control study with secondary data. J Epidemiol Community Health 2008; 63:233–238.

14• Saraceni V, King BS, Cavalcante SC, et al. Tuberculosis as primary cause of death among AIDS cases in Rio de Janeiro, Brazil. Int J Tuberc Lung Dis 2008; 12:769–772.

15• Lopez-Gatell H, Cole SR, Margolick JB, et al. Effect of tuberculosis on the survival of HIV-infected men in a country with low tuberculosis incidence. AIDS 2008; 22:1869–1873.

16 Lopez-Gatell H, Cole SR, Hessol NA, et al. Effect of tuberculosis on the survival of women infected with human immunodeficiency virus. Am J Epidemiol 2007; 165:1134–1142.

17• Martinson NA, Karstaedt A, Venter WD, et al. Causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study. AIDS 2007; 21:2043–2050.

18 Panjabi R, Comstock GW, Golub JE. Recurrent tuberculosis and its risk factors: adequately treated patients are still at high risk. Int J Tuberc Lung Dis 2007; 11:828–837.

19•• Golub JE, Durovni B, King BS, et al. Recurrent tuberculosis in HIV-infected patients in Rio de Janeiro, Brazil. AIDS 2008; 22:2527–2533.

20• Charalambous S, Grant AD, Moloi V, et al. Contribution of reinfection to recurrent tuberculosis in South African gold miners. Int J Tuberc Lung Dis 2008; 12:942–948.

21• Nahid P, Gonzalez LC, Rudoy I, et al. Treatment outcomes of patients with HIV and tuberculosis. Am J Respir Crit Care Med 2007; 175:1199–1206.

22 Sonnenberg P, Murray J, Glynn JR, et al. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001; 358:1687–1693.

23 Churchyard GJ, Fielding K, Charalambous S, et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected southern Africans: time to change policy? AIDS 2003; 17:2063–2070.

24 Lawn SD, Bekker LG, Middelkoop K, et al. Impact of HIV infection on the epidemiology of tuberculosis in a peri-urban community in South Africa: the need for age-specific interventions. Clin Infect Dis 2006; 42:1040–1047.

25•• Glynn JR, Murray J, Bester A, et al. Effects of duration of HIV infection and secondary tuberculosis transmission on tuberculosis incidence in the South African gold mines. AIDS 2008; 22:1859–1867.

26•• Middelkoop K, Bekker LG, Myer L, et al. Rates of tuberculosis transmission to children and adolescents in a community with a high prevalence of HIV infection among adults. Clin Infect Dis 2008; 47:349–355.

27• Wood R, Middelkoop K, Myer L, et al. Undiagnosed tuberculosis in a community with high HIV prevalence: implications for tuberculosis control. Am J Respir Crit Care Med 2007; 175:87–93.

28 Corbett EL, Charalambous S, Moloi VM, et al. Human immunodeficiency virus and the prevalence of undiagnosed tuberculosis in African gold miners. Am J Respir Crit Care Med 2004; 170:673–679.

29•• Corbett EL, Bandason T, Cheung YB, et al. Epidemiology of tuberculosis in a high HIV prevalence population provided with enhanced diagnosis of symptomatic disease. PLoS Med 2007; 4:e22.

30 Lawn SD, Bangani N, Vogt M, et al. Utility of interferon-gamma ELISPOT assay responses in highly tuberculosis-exposed patients with advanced HIV infection in South Africa. BMC Infect Dis 2007; 7:99.

31 Rangaka MX, Wilkinson KA, Seldon R, et al. Effect of HIV-1 infection on T-cell-based and skin test detection of tuberculosis infection. Am J Respir Crit Care Med 2007; 175:514–520.

32 Hanifa Y, Grant AD, Lewis J, et al. Prevalence of latent tuberculosis infection among gold miners in South Africa. Int J Tuberc Lung Dis 2009; 13:39–46.

33 Corbett EL, Charalambous S, Fielding K, et al. Stable incidence rates of tuberculosis (TB) among human immunodeficiency virus (HIV)-negative South African gold miners during a decade of epidemic HIV-associated TB. J Infect Dis 2003; 188:1156–1163.

34 Zignol M, Hosseini MS, Wright A, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006; 194:479–485.

35•• Wells CD, Cegielski JP, Nelson LJ, et al. HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis 2007; 196(Suppl 1):S86–S107.

36• Dubrovina I, Miskinis K, Lyepshina S, et al. Drug-resistant tuberculosis and HIV in Ukraine: a threatening convergence of two epidemics? Int J Tuberc Lung Dis 2008; 12:756–762.

37 Shah NS, Pratt R, Armstrong L, et al. Extensively drug-resistant tuberculosis in the United States, 1993–2007. JAMA 2008; 300:2153–2160.

38 Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368:1575–1580.

39• Andrews JR, Gandhi NR, Moodley P, et al. Exogenous reinfection as a cause of multidrug-resistant and extensively drug-resistant tuberculosis in rural South Africa. J Infect Dis 2008; 198:1582–1589.

40• Pillay M, Sturm AW. Evolution of the extensively drug-resistant F15/LAM4/KZN strain of Mycobacterium tuberculosis in Kwazulu-Natal, South Africa. Clin Infect Dis 2007; 45:1409–1414.

41 Singh JA, Upshur R, Padayatchi N. XDR-TB in South Africa: no time for denial or complacency. PLoS Med 2007; 4:e50.

42 Andrews JR, Shah NS, Gandhi N, et al. Multidrug-resistant and extensively drug-resistant tuberculosis: implications for the HIV epidemic and antiretroviral therapy rollout in South Africa. J Infect Dis 2007; 196(Suppl 3):S482–S490.

43 Escombe AR, Oeser C, Gilman RH, et al. The detection of airborne transmission of tuberculosis from HIV-infected patients, using an in vivo air sampling model. Clin Infect Dis 2007; 44:1349–1357.

44•• Escombe AR, Moore DA, Gilman RH, et al. The infectiousness of tuberculosis patients coinfected with HIV. PLoS Med 2008; 5:e188.

45 Lawn SD, Myer L, Bekker LG, Wood R. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control. AIDS 2006; 20:1605–1612.

46 Moore D, Liechty C, Ekwaru P, et al. Prevalence, incidence and mortality associated with tuberculosis in HIV-infected patients initiating antiretroviral therapy in rural Uganda. AIDS 2007; 21:713–719.

47 Lawn SD, Edwards D, Wood R. Tuberculosis transmission from patients with smear-negative pulmonary tuberculosis in sub-Saharan Africa. Clin Infect Dis 2009; 48:496–497.

48 Joshi R, Reingold AL, Menzies D, Pai M. Tuberculosis among health-care workers in low- and middle-income countries: a systematic review. PLoS Med 2006; 3:e494.

49• Corbett EL, Muzangwa J, Chaka K, et al. Nursing and community rates of Mycobacterium tuberculosis infection among students in Harare, Zimbabwe. Clin Infect Dis 2007; 44:317–323.

50 Menzies D, Joshi R, Pai M. Risk of tuberculosis infection and disease associated with work in healthcare settings. Int J Tuberc Lung Dis 2007; 11:593–605.

51•• Galgalo T, Dalal S, Cain KP, et al. Tuberculosis risk among staff of a large public hospital in Kenya. Int J Tuberc Lung Dis 2008; 12:949–954.

52• Bock NN, Jensen PA, Miller B, Nardell E. Tuberculosis infection control in resource-limited settings in the era of expanding HIV care and treatment. J Infect Dis 2007; 196(Suppl 1):S108–S113.

53• Escombe AR, Oeser CC, Gilman RH, et al. Natural ventilation for the prevention of airborne contagion. PLoS Med 2007; 4:e68.

54•• Escombe AR, Moore DA, Gilman RH, et al. Upper-room ultraviolet light and negative air ionization to prevent tuberculosis transmission. PLoS Med 2009; 6:e43.

55•• Basu S, Andrews JR, Poolman EM, et al. Prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: an epidemiological modelling study. Lancet 2007; 370:1500–1507.

56 Akksilp S, Karnkawinpong O, Wattanaamornkiat W, et al. Antiretroviral therapy during tuberculosis treatment and marked reduction in death rate of HIV-infected patients, Thailand. Emerg Infect Dis 2007; 13:1001–1007.

57 Sanguanwongse N, Cain KP, Suriya P, et al. Antiretroviral therapy for HIV-infected tuberculosis patients saves lives but needs to be used more frequently in Thailand. J Acquir Immune Defic Syndr 2008; 48:181–189.

58 Velasco M, Castilla V, Sanz J, et al. Effect of simultaneous use of highly active antiretroviral therapy on survival of HIV patients with tuberculosis. J Acquir Immune Defic Syndr 2009; 50:148–152.

59 Bong CN, Chen SC, Jong YJ, et al. Outcomes of HIV-infected children with tuberculosis who are started on antiretroviral therapy in Malawi. Int J Tuberc Lung Dis 2007; 11:534–538.

60 Makombe SD, Harries AD, Yu JK, et al. Outcomes of tuberculosis patients who start antiretroviral therapy under routine programme conditions in Malawi. Int J Tuberc Lung Dis 2007; 11:412–416.

61 Zachariah R, Fitzgerald M, Massaquoi M, et al. Does antiretroviral treatment reduce case fatality among HIV-positive patients with tuberculosis in Malawi? Int J Tuberc Lung Dis 2007; 11:848–853.

62 Lawn SD, Wood R. When should antiretroviral treatment be started in patients with HIV-associated tuberculosis in South Africa? S Afr Med J 2007; 97:414–415, 414-2, 415.

63 Yu JK, Bong CN, Chen SC, et al. Outcomes in HIV-infected patients who develop tuberculosis after starting antiretroviral treatment in Malawi. Int J Tuberc Lung Dis 2008; 12:692–694.

64 Lawn SD, Badri M, Wood R. Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort. AIDS 2005; 19:2109–2116.

65 Lawn SD, Harries AD, Anglaret X, et al. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS 2008; 22:1897–1908.

66 Zachariah R, Fitzgerald M, Massaquoi M, et al. Risk factors for high early mortality in patients on antiretroviral treatment in a rural district of Malawi. AIDS 2006; 20:2355–2360.

67 Westreich D, MacPhail P, Van Rie A, et al. Effect of pulmonary tuberculosis on mortality in patients receiving HAART. AIDS 2009; 23:707–715.

68 Blanc FX, Havlir DV, Onyebujoh PC, et al. Treatment strategies for HIV-infected patients with tuberculosis: ongoing and planned clinical trials. J Infect Dis 2007; 196(Suppl 1):S46–S51.

69 Lawn SD, Bekker LG, Wood R. How effectively does HAART restore immune responses to Mycobacterium tuberculosis? Implications for tuberculosis control. AIDS 2005; 19:1113–1124.

70 Muga R, Ferreros I, Langohr K, et al. Changes in the incidence of tuberculosis in a cohort of HIV-seroconverters before and after the introduction of HAART. AIDS 2007; 21:2521–2527.

71 Moreno S, Jarrin I, Iribarren JA, et al. Incidence and risk factors for tuberculosis in HIV-positive subjects by HAART status. Int J Tuberc Lung Dis 2008; 12:1393–1400.

72•• Golub JE, Saraceni V, Cavalcante SC, et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS 2007; 21:1441–1448.

73 Miranda A, Morgan M, Jamal L, et al. Impact of antiretroviral therapy on the incidence of tuberculosis: the Brazilian experience, 1995–2001. PLoS ONE 2007; 2:e826.

74• Walters E, Cotton MF, Rabie H, et al. Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on antiretroviral therapy. BMC Pediatr 2008; 8:1.

75• Brinkhof MW, Egger M, Boulle A, et al. Tuberculosis after initiation of antiretroviral therapy in low-income and high-income countries. Clin Infect Dis 2007; 45:1518–1521.

76 Williams BG, Dye C. Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS. Science 2003; 301:1535–1537.

77 Pacheco AG, Durovni B, Cavalcante SC, et al. AIDS-related tuberculosis in Rio de Janeiro, Brazil. PLoS ONE 2008; 3:e3132.

78 Grant AD, Charalambous S, Fielding KL, et al. Effect of routine isoniazid preventive therapy on tuberculosis incidence among HIV-infected men in South Africa: a novel randomized incremental recruitment study. JAMA 2005; 293:2719–2725.

79 Hoffmann CJ, Charalambous S, Thio CL, et al. Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B. AIDS 2007; 21:1301–1308.

80 Atun RA, Lebcir RM, Drobniewski F, et al. High coverage with HAART is required to substantially reduce the number of deaths from tuberculosis: system dynamics simulation. Int J STD AIDS 2007; 18:267–273.

81 Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5:361–373.

82• Murdoch DM, Venter WD, Feldman C, Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008; 22:601–610.

83• Lawn SD, Lipman MC, Easterbrook PJ. Immune reconstitution disease associated with mycobacterial infections. Curr Opin HIV AIDS 2008; 3:425–431.

84• Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008; 8:516–523.

85•• Lawn SD, Myer L, Bekker LG, Wood R. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007; 21:335–341. This was the first study to report on rates, risk factors and clinical presentations of TB IRD in an African cohort. The study highlighted the major importance of the timing of ART initiation; those initiating ART in the first month of TB treatment have a 70-fold higher risk than those initiating ART after at least 3 months of TB treatment.

86 Burman W, Weis S, Vernon A, et al. Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis. Int J Tuberc Lung Dis 2007; 11:1282–1289.

87• Lawn SD, Wilkinson RJ, Lipman MC, Wood R. Immune reconstitution and ‘unmasking’ of tuberculosis during antiretroviral therapy. Am J Respir Crit Care Med 2008; 177:680–685.

88 Manabe YC, Breen R, Perti T, et al. Unmasked tuberculosis and tuberculosis immune reconstitution inflammatory disease: a disease spectrum after initiation of antiretroviral therapy. J Infect Dis 2009; 199:437–444.

89 Lawn SD, Wainwright H, Orrell C. Fatal unmasking tuberculosis immune reconstitution disease with bronchiolitis obliterans organizing pneumonia: the role of macrophages. AIDS 2009; 23:143–145.

90• Lonnroth K, Raviglione M. Global epidemiology of tuberculosis: prospects for control. Semin Respir Crit Care Med 2008; 29:481–491.

Keywords:

antiretroviral; epidemiology; HIV; tuberculosis

© 2009 Lippincott Williams & Wilkins, Inc.

Login

Article Level Metrics

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.