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•].
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 .
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 . 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 .
Consistent with previous randomized clinical trials, cotrimoxazole prophylaxis significantly reduced mortality risk in HIV-infected pulmonary TB patients in Zambia . Together with post-mortem data from South Africa [17•], these data highlight bacterial sepsis as a likely frequent cause of death in these patients.
The WHO DOTS strategy has proven insufficient to control TB in high HIV prevalence communities in southern Africa . 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  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 . 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 . Collectively, these data suggest that the contribution of HIV-TB to transmission is variable and may be age-specific.
Approximately 425 000 MDR-TB cases occur annually worldwide, representing nearly 5% of the world's annual TB burden . 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 .
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 . 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  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 . 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 . 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.
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 .
The risk of TB among healthcare workers in low-income and middle-income countries is an increasingly recognized problem . 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 . 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.
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.
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 . In Thailand [56,57] and Spain , 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 . Furthermore, most deaths occurred in the intensive phase of TB treatment , suggesting the need for early ART initiation . Consistent with data from South Africa , patients developing incident TB during ART in Malawi have much poorer survival . This reflects the fact that TB develops opportunistically in those patients with poor CD4 cell recovery and who already have poor survival .
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 , 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•].
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 . TB accounted for 41% of IRD events in a prospective South African cohort [82•].
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 .
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 .
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.
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.
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