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J Int AIDS Soc. 2012; 15(2): 17396.
Published online Jul 27, 2012. doi:  10.7448/IAS.15.2.17396
PMCID: PMC3499795
HIV and tuberculosis – science and implementation to turn the tide and reduce deaths
Anthony D Harries,§1,2 Stephen D Lawn,2,3 Haileyesus Getahun,4 Rony Zachariah,5 and Diane V Havlir6
1International Union Against Tuberculosis and Lung Disease, Paris, France
2Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
3Desmond Tutu HIV Centre, Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
4Stop TB Department, World Health Organization, Geneva, Switzerland
5Medecins sans Frontieres, Medical Department, Operational Research Unit, Brussels Operational Center, Luxembourg, Luxembourg
6Division of HIV/AIDS, University of California San Francisco, CA, USA
§Corresponding author: Anthony D Harries, Old Inn Cottage, Vears Lane, Colden Common, Winchester SO21 1TQ, UK. Tel: +44 (0) 1962 714 297. (adharries/at/theunion.org)
Received April 24, 2012; Accepted July 5, 2012.
Introduction
Every year, HIV-associated tuberculosis (TB) deprives 350,000 mainly young people of productive and healthy lives. People die because TB is not diagnosed and treated in those with known HIV infection and HIV infection is not diagnosed in those with TB. Even in those in whom both HIV and TB are diagnosed and treated, this often happens far too late. These deficiencies can be addressed through the application of new scientific evidence and diagnostic tools.
Discussion
A strategy of starting antiretroviral therapy (ART) early in the course of HIV infection has the potential to considerably reduce both individual and community burden of TB and needs urgent evaluation for efficacy, feasibility and broader social and economic impact. Isoniazid preventive therapy can reduce the risk of TB and, if given strategically in addition to ART, provides synergistic benefit. Intensified TB screening as part of the “Three I's” strategy should be conducted at every clinic, home or community-based attendance using a symptoms-based algorithm, and new diagnostic tools should increasingly be used to confirm or refute TB diagnoses. Until such time when more sensitive and specific TB diagnostic assays are widely available, bolder approaches such as empirical anti-TB treatment need to be considered and evaluated. Patients with suspected or diagnosed TB must be screened for HIV and given cotrimoxazole preventive therapy and ART if HIV-positive. Three large randomized trials provide conclusive evidence that ART initiated within two to four weeks of start of anti-TB treatment saves lives, particularly in those with severe immunosuppression. The key to ensuring that these collaborative activities are delivered is the co-location and integration of TB and HIV services within the health system and the community.
Conclusions
Progress towards reducing HIV-associated TB deaths can be achieved through attention to simple and deliverable actions on the ground.
John Donne, Meditation XVII, Devotions upon Emergent Occasions:
… any mans death diminishes me because I am involved in Mankinde; And therefore never send to know for whom the bell tolls; it tolls for thee ….
Keywords: HIV, tuberculosis, antiretroviral therapy, intensified case finding, isoniazid preventive therapy, mortality
In 2010, an estimated 34 million adults and children were living with HIV/AIDS [persons living with HIV (PLHIV)] worldwide: 1.1 million had HIV-associated tuberculosis (TB) and 350,000 with HIV-associated TB died [1]. Given that TB is a curable disease and that HIV/AIDS can now be treated, albeit with life-long drug therapy, why did this high mortality occur? People died for three main reasons: (i) TB was not diagnosed in those known to have HIV infection and who were accessing antiretroviral therapy (ART); (ii) HIV was not diagnosed in those with TB and therefore these patients were not offered HIV care and treatment, and (iii) when the two diseases were diagnosed and treated, these interventions happened far too late. The application of new scientific evidence and strategic use of new diagnostic tools make it possible to address these gaps and dramatically reduce the mortality caused by HIV-associated TB.
Epidemiology
In 2010, 82% of the global burden of HIV-associated TB and 71% of the associated deaths occurred in sub-Saharan Africa, with 10 countries in the southern region of Africa accounting for more than 50% of cases [1]. Although HIV-associated TB is a global problem, other focal points are South Asia (India, Thailand, Indonesia and Myanmar) and Eastern Europe (Ukraine and the Russian Federation) where intravenous drug use drives the co-epidemic.
The scale up of ART over the last seven years has been a remarkable, and deservedly applauded, success, with over 6.6 million people (5.1 million in sub-Saharan Africa) estimated to be receiving treatment in low- and middle-income countries [2]. However, between 8% and 26% of patients die in the first year of treatment [3], and both diagnosed and undiagnosed TB are recognized as major causes of this mortality. Autopsy studies conducted in sub-Saharan Africa before and during the ART era in adult HIV-infected hospitalized patients found that TB, particularly disseminated disease, was responsible for 40% to 50% of deaths (Table 1) [47]. A more recent study in South Africa in HIV-positive adults also showed that high proportion of patients who died in the first six months of receiving ART had disseminated TB [8].
Table 1
Table 1
Causes of death in HIV-infected patients on medical wards – autopsy studies from sub-Saharan Africa
Similarly, TB patients diagnosed with HIV and not receiving HIV treatment have a high case fatality, which occurs early during the course of anti-TB treatment [9], is generally higher in smear-negative TB [10] and increases as the CD4 count decreases (Table 2) [1,11,12]. Early diagnosis, treatment and prevention of TB in PLHIV and early diagnosis and treatment of HIV in TB patients are essential if these deaths are to be avoided [13].
Table 2
Table 2
Case fatality in HIV-infected smear-positive pulmonary TB patients before the era of antiretroviral therapy
The 2012 WHO policy on collaborative TB/HIV activities
In March 2012, the World Health Organization (WHO) released an updated policy on collaborative TB/HIV activities, which consolidates evidence collated over the last six years from randomized controlled trials, observational studies, operational research and best practices from programme implementation [14]. It follows the same framework as the 2004 interim policy document [15], structuring 12 activities under three distinct objectives (Table 3), but with some important differences. These include (i) recognition of the crucial role of early ART initiation in preventing TB in PLHIV, (ii) expanded use of HIV testing and HIV prevention to include patients with presumptive TB as well as partners and family members of patients with TB and (iii) more guidance for the integration of HIV and TB services in time and place and with other health programmes.
Table 3
Table 3
WHO policy on recommended collaborative TB/HIV activities, 2012
It is estimated that one million lives have been saved between 2005 and 2010 as a result of implementing key activities of the 2004 interim policy [16], and adoption of the new policy should bring even greater benefit. Five important spheres of work are needed to reduce HIV-TB mortality: (i) preventing TB in PLHIV by early ART and isoniazid preventive therapy (IPT); (ii) finding, diagnosing and treating tuberculosis in PLHIV; (iii) diagnosing and treating HIV in people with presumptive and diagnosed TB, including drug-resistant TB; (iv) addressing these challenges in children; and (v) ensuring that HIV/TB services are co-located and/or integrated within health facilities and the community.
Preventing TB in PLHIV: early ART and IPT
Antiretroviral therapy
There is now compelling evidence that ART is a powerful preventive agent for TB in PLHIV. A systematic review and meta-analysis of studies in cohorts of PLHIV from around the world have shown that ART significantly reduces rates of TB, with effects most apparent in patients with more advanced HIV-disease or with the lowest CD4 counts (Table 4) [17]. At the individual level, these beneficial effects increase with length of time on ART, although they never decrease to a level that approaches the rates of TB seen in patients without HIV-infection [18,19]. At the programme level, it has also been shown in rural Malawi [20] and Cape Town, South Africa [21], that when ART coverage in a population reaches a high level of coverage, TB notification rates in that population decrease, and in Malawi, this reduction was noted for both new and recurrent TB (Table 5) [20].
Table 4
Table 4
Reduction in the incidence rate ratio of TB in people living with HIV and started on ART
Table 5
Table 5
Effect of ART scale up on TB case notification rates in a rural district, Malawi
Definitive evidence of the protective effect of ART at higher baseline CD4 counts is provided in randomized controlled trials. In a study in Haiti, TB incidence was reduced by 50% in patients starting ART at CD4 counts between 200 and 350 cells/µL compared with those starting ART when the CD4 count dropped to below 200 cells/µL or when treatment was deferred until the onset of AIDS [22]. This reduction in TB incidence was matched by a 75% reduction in the risk of death for those starting ART early. These data informed the 2010 revision of the WHO ART Guidelines [23] that recommend starting ART at CD4 counts<350 cells/µL. Evidence for the TB protective effect of ART at even higher CD4 counts came from a recent HIV Prevention Trials Network (HPTN 052) study [24] in which there was a 40% reduction in serious HIV-related clinical events or death in PLHIV starting ART at CD4 counts from 350 to 550 cells/µL compared with those initiating ART at CD4 counts≤250 cells/µL or when AIDS had developed. The difference in incidence of clinical events was driven mainly by extrapulmonary TB (EPTB), which developed in three patients in the early-therapy group and 17 in the delayed-therapy group.
Mathematical models predict the enormous benefit that early ART initiation might have on TB prevention [25]. In a model using data from the South African HIV/AIDS epidemic, universal and annual HIV testing of adults linked to immediate start of ART in those HIV-positive could lead to a halving in incidence of HIV-associated TB within five years and a reduction by 95% within 40 years [26]. The strategy works in two ways: a direct effect for the individual through immune reconstitution and an indirect effect for the community by reducing HIV transmission, resulting in fewer people infected with HIV and, therefore, being at risk of HIV-associated TB.
Identification of HIV infection early in the course of disease when CD4 counts are still high is essential for maximizing the protective effect of ART for TB. In sub-Saharan Africa, most patients are diagnosed with HIV and start ART at low CD4 counts of 100 to 150 cells/µL, while the majority of HIV-associated TB patients are diagnosed at higher CD4 counts of 150 to 200 cells/µL [13,18]. Thus, HIV diagnosis and initiation of ART are generally too late to prevent TB, and the TB preventive role of ART is largely squandered. Further and urgent research is now needed to assess efficacy, feasibility, safety, cost, social and population uptake and effect of the “Test and Treat” approach where the linkage of HIV testing to CD4 count measurements, a barrier to ART access in many low-income countries, is removed. Several randomized controlled trials are underway [27], and in some countries like Malawi, the strategy is already being implemented at country level for pregnant women [28].
Isoniazid preventive therapy
IPT is another essential intervention for TB prevention. Given daily for six months, it reduces the overall risk of TB in PLHIV by 33%, with the protective effect confined to those with a positive tuberculin skin test (TST) in whom the risk reduction is 64% [29]. Based on this evidence, WHO guidelines between 1998 and 2009 emphasized that IPT should be used as prophylaxis in PLHIV who are TST-positive [30].
However, implementation has been poor with the two major stumbling blocks being the process of TST assessment and reliable exclusion of active TB. To overcome this inertia, the revised WHO IPT guidelines made a strong explicit recommendation that “TST is not a requirement for initiating IPT in people living with HIV” although it “can be used where feasible” [31]. Implementation is improving, and by the end of 2010, about one-quarter of PLHIV enrolled in care and eligible for IPT on the basis of negative symptom screening were started on TB preventive therapy [1].
The duration of treatment is currently recommended for at least six months [31]. New data on the optimal duration of IPT could improve the overall effectiveness of this intervention, although this will raise additional challenges for IPT delivery. In Botswana, 36 months of IPT reduced TB incidence by 43% compared with six months of IPT, the effects again being most apparent in TST-positive persons [32]. After cessation of IPT, TB incidence increased [33], even in the presence of ART, suggesting that continued isoniazid in these settings with high TB burden and transmission is necessary to maintain a TB preventive effect. Based on these and other data, the new WHO Guidelines recommend that, in countries with high rates of community TB transmission, such as in southern Africa, consideration should be given to extended treatment for 36 months or longer [31], and evidence is beginning to suggest that IPT should be life long.
An area of ongoing research and debate is the optimal timing and use of IPT and ART. Observational studies from Brazil [34] and South Africa [35] and the data from Botswana [32] suggest that sequential or concurrent use of ART and IPT results in a synergistic decline in risk of active TB. Randomized placebo-controlled data regarding the additive beneficial effects of this combined approach are awaited from the ANRS TEMPRANO trial in Core d'Ivoire [NCT00495651] and the HAART-IPT trial in South Africa [NCT00463086] [27]. However, in the interim and within the structured set up of an ART clinic, an implementable strategy could be the introduction and continuation of IPT once patients are stable, asymptomatic and prevalent TB has been unmasked [36].
Finding, diagnosing and treating TB in PLHIV
Intensified TB case finding
Linked to the prevention of TB with use of IPT is the need to reliably find and diagnose active TB disease, and this is packaged together under the acronym “The Three I's” (intensified case finding, isoniazid preventive therapy and infection control). Good progress has been made with intensified TB case finding (ICF) in terms of the development of a standardized screening tool [37] and indicators for monitoring progress [38]. A standardized screening tool, developed as a result of meta-analysis of available data, focusses on four key questions: current cough of any duration and a history of unintentional weight loss, night sweats and fever in the last four weeks [37]. This is being used in the field, and for example, in one study amongst HIV-infected pregnant women, these questions were found to be acceptable, feasible and associated with a high negative predictive value [39]. In patient groups with the very highest TB prevalence rates exceeding 10%, the negative predictive value would be somewhat lower.
Available data show that about 50% of PLHIV being screened have one or more positive symptoms, and 10% of those with a positive screen may be subsequently diagnosed with TB [37], with the numbers needed to screen and the yield of active TB being dependent on prevalence of endemic TB, the setting and the diagnostic methods used [40]. A small proportion (1% to 2%) of asymptomatic PLHIV have microbiologically confirmed TB [37], although between 50% and 75% of such patients develop symptoms over the subsequent few months [41,42].
These findings have implications for the programme setting. In 2010, an estimated 2.3 million PLHIV (58% of those enrolled in care) were screened for TB [1]. With the new and simpler screening recommendations, these numbers will undoubtedly increase. Symptom screening must be done at baseline in all PLHIV attending pre-ART or ART clinics. Screening should also not be a one-off event but performed serially when PLHIV come to the clinic to prevent the small proportion of asymptomatic patients with TB from slipping through the net as well as to detect the high ongoing incidence of new disease that persists long-term during ART. In the busy, understaffed ART clinics of sub-Saharan Africa, it is important to address simple operational questions about how often and when best to do this symptom screening so as not to overwhelm the already high workload. Laboratory capacity and appropriate quality assurance must also develop in parallel to manage the increase in referrals.
The usual method of investigating for TB is with sputum smear microscopy followed by chest radiography in those with negative sputum smears. While this system has been the mainstay for TB diagnosis for years, it is time consuming, costly for the patient who needs to make multiple journeys to the clinic and diagnostically insensitive [43,44]. This is especially true for HIV-infected TB patients in whom a significant proportion have negative sputum smears and a normal chest x-ray at very low CD4 counts<50 cells/µL [45]. Without facilities for culture of Mycobacterium tuberculosis (MTB), and this is the case in most resource-poor settings, it is easy to miss the diagnosis of TB. There is an urgent need for more accurate, inexpensive, quick point-of-care tests for diagnosing TB.
The most important and revolutionary diagnostic development to date is a sensitive and specific fully automated and commercially available nucleic acid amplification test, the Xpert MTB/RIF assay (Cepheid, Inc., Sunnyvale, CA, USA) for use with sputum and other body specimens [46]. Xpert MTB/RIF uses a common platform to detect TB and rifampicin resistance. The cartridge-based system dispenses with the need for prior sputum processing, requires minimal laboratory expertise and results are provided in an automated manner in less than two hours. Sensitivity for one sputum specimen for smear-positive PTB is high at 98%, and for smear-negative PTB in whom sputum bacillary numbers are low, sensitivities are 72%, 85% and 90% for one, two or three specimens, respectively [46]. When used to investigate suspected EPTB using samples from a wide range of anatomic locations, Xpert MTB/RIF provides a rapid TB diagnosis in over two-thirds of cases but with a wide range of sensitivity (25% to 97%). Sensitivity is notably lower from body fluids in which mycobacterial load is likely to be very low such as pleural, pericardial and peritoneal fluid [47].
In December 2010, WHO strongly recommended that Xpert MTB/RIF be used as the initial diagnostic test in persons suspected of HIV-associated TB. By early 2012, over 450 Xpert instruments had been placed in 47 countries, and work is ongoing to assess feasibility, accuracy and effectiveness at district and sub-district health facilities [48]. The machine's functionality in these settings will depend on various operational factors that include cost, temperatures, shelf-life of cartridges, electricity supplies, maintenance and the need for annual calibration of the machine. The machine's impact will depend on how effective and timely is the linkage between the patient, the diagnosis and subsequent treatment. Data from South Africa illustrate that, when the technology is separated from the patient because of distance or related factors, the resulting gap significantly undermines the potential to improve patient outcomes [49].
Another promising test that might be useful in severe immune suppression, which is often associated with disseminated MTB, is the measurement of urine lipoarabinomannan (LAM), one of the cell wall lipopolysaccharide components of MTB. This can be measured either with an ELISA or more easily with a Determine TB-LAM test strip (Alere, Waltham, MA, USA), the latter costing $3.50 per test strip and producing a result in 30 minutes. This offers the real possibility of point-of-care testing. In HIV-infected patients, specificity is high at over 95% for all CD4 strata. Useful sensitivity is observed in those with CD4 counts<200 cells/µL, but progressively increases as the CD4 count decreases, reaching over two-thirds in those with CD4 counts<50 to 100 cells/µL [50,51].
Further work will determine the most feasible screening and diagnostic algorithm for PLHIV in these clinic settings. This will most probably be a combination of tests that include sputum smears (to identify those with infectious TB), urine LAM (to identify TB patients with the most advanced immune suppression) and Xpert MTB/RIF, for which operational research is urgently needed to determine how far peripherally the test can be decentralized to bring it as close to the patient as possible. Accurate and timely diagnosis of TB in the setting of HIV clinics has, and continues to be, the Achilles heel of the Three I's where it is important not only to diagnose and treat TB but also exclude TB so that TB preventive therapy can be safely implemented.
Empirical anti-TB treatment
Faced with the current difficulties of implementing ICF and IPT and of diagnosing TB in PLHIV with low CD4 counts, it is reasonable to consider the option of empirical anti-TB treatment in high HIV-TB burden settings [52]. The rationale is that as the CD4 count decreases, the risk of TB exponentially increases, and at a certain point, there is more to gain than lose in treating empirically for TB (Table 6). Two randomized controlled trials [PROMPT (NCT01417988) and REMEMBER (NCT01380080)] [27] are currently underway to test whether this strategy has a high benefit-to-risk ratio in PLHIV about to start ART and whether the intervention is associated with a reduction in early and long-term mortality. A final caveat is that empirical anti-TB treatment in settings where drug resistance is high adds complexity to this approach and to subsequent research study designs if the two trials underway show positive benefit.
Table 6
Table 6
Potential benefits from empirical antituberculosis treatment in persons living with HIV who are severely immune suppressed
Diagnosing and treating HIV in patients with diagnosed and presumptive TB
If we fail to prevent TB, it is important that PLHIV who develop active TB are diagnosed and treated for HIV/AIDS. The key interventions include the use of cotrimoxazole preventive therapy (CPT) and ART, provided early and promptly in the course of anti-TB treatment. CPT is safe, cheap, easy to administer and associated with significant decreases in mortality of between 25% and 46% [5358]. CPT can also be used before and in combination with ART, with observational and clinical studies showing 40% reductions in early mortality and overall increases in life expectancy [5961]. ART is essential to the prognosis of patients with HIV-associated TB: mortality risk is reduced by 64% and 95%, there are excellent immunological/virological responses and a reduction in recurrent TB [6264].
The management algorithm is straightforward (Figure 1), and provider-initiated HIV testing and counseling (PITC), CPT and ART are the basic standard of care.
Figure 1
Figure 1
Management algorithm for HIV-associated TB.
Provider-initiated HIV testing and counselling
The HIV test is the gateway to HIV care and treatment. It establishes the diagnosis and is an important component of efforts to prevent HIV transmission. WHO recommends that PITC is provided on a routine basis [65], and this service, delivered largely through point-of-care HIV diagnostics using dipstick technology, is feasible and acceptable in most settings [66,67]. Good progress has been made in the HIV testing of TB patients, with the proportion of new and retreatment TB cases HIV tested rising from less than 5% in 2004 to 34% in 2010 [1]. Some regions do better than others – in 2010, HIV testing reached 59% of notified TB cases in Africa and 80% in Europe [1].
Two additional issues merit comment. First, in the routine programme setting, false-positive and false-negative HIV test results occur, and programmes need to decide on whether they do serial or parallel testing, the need for confirmatory tests and how to implement quality assurance. Second, studies in East Africa, Guinea-Bissau and Zimbabwe [6871] indicate the importance of moving HIV testing upstream to include patients with suspected TB and ensuring that those who are smear-negative can be referred for HIV care and consideration of ART. In Zimbabwe, 63% of patients suspected of PTB who were found to be smear-negative were HIV-positive and the majority had CD4 cell counts<350 cells/µL [71]. During 12-month follow-up, 18% were diagnosed as having TB, only 15% were started on ART and 12% of the cohort was known to have died. In line with new WHO recommendations [14], these poor outcomes could be avoided if patients with suspected TB, and this applies to partners and family members, were routinely HIV tested and those found HIV-positive linked to structured HIV care and treatment that included TB screening.
Antiretroviral therapy
ART is an essential intervention for the management of HIV-associated TB. The Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) trial clearly showed that across a range of CD4 counts it was better to start ART during anti-TB treatment than to wait until TB treatment had been completed [72], and these data informed the 2010 WHO ART guidelines recommending that all HIV-positive TB patients are eligible for ART, regardless of CD4 count [23].
The issue of optimal timing of ART in relation to start of anti-TB treatment has been clarified by three randomized controlled studies: CAMELIA, STRIDE and SAPIT [7375]. While all three trials were slightly different – median CD4 counts at baseline ranged from 25 cells/µL in Cambodia to 150 cells/µL in South Africa, and there were different working definitions of TB – collectively, one clear message emerges, namely that earlier initiation of ART saves lives in HIV-infected patients with TB. These benefits were particularly evident for those with CD4 cell counts<50 cells/µL in whom the risk of HIV infection or death was minimized by starting ART within the first two to four weeks of TB treatment. These and subsequent studies [76,77] show that the risk of immune reconstitution inflammatory syndrome (IRIS) is increased, especially in those with low CD4 counts, but this is counterbalanced by improved survival. One exception is in HIV-infected patients with TB meningitis in whom early ART is not associated with improved survival, probably because of the devastating effects of IRIS within the confined space of the central nervous system [78].
In many low-income countries, CD4 count testing remains an obstacle to accessing HIV care and treatment, and insistence on its use will reduce ART uptake. However, where facilities for measurement do exist, knowledge of the CD4 count would allow a more rational guide as to whether ART is started within two weeks or between two and eight weeks of the start of anti-TB treatment.
There are no important drug-drug interactions between first-line ART and standard anti-TB treatment, provided efavirenz is used as the non-nucleoside reverse transcriptase inhibitor. However, protease inhibitors, used in most second-line ART regimens, cannot be administered with rifampicin. Rifabutin has minimal effects on serum levels of protease inhibitors and is therefore a potentially safe and effective agent to maintain rifamycin-based anti-TB treatment with second-line ART [79]. To date, however, issues such as cost, lack of fixed-dose combination pills and lack of registration in many countries preclude its use in current routine management.
ART and drug-resistant TB
In the absence of ART, HIV-infected patients with multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) have high case fatality rates [8082]. With the rollout of Xpert MTB/RIF assay as the recommended diagnostic test in HIV-infected patients with suspected TB, it is likely that the number of patients diagnosed with MDR-TB will increase dramatically. The earlier detection of MDR-TB should in itself improve prognosis provided there is ready access to appropriate second-line anti-TB treatment, as most MDR-TB patients in low-income countries are diagnosed late, usually only when they fail or relapse on standard anti-TB treatment.
Observational cohort studies have shown that ART improves survival of HIV-infected patients with MDR-TB [83] and XDR-TB [84], and ART should be started as early as possible in combination with CPT [85]. Early ART combined with often advanced clinical disease puts patients at increased risk of TB-IRIS in addition to frequent drug interactions and co-toxicities [86]. With promising new TB drug compounds on the horizon to treat drug-sensitive and drug-resistant TB, it will be essential to include patients with HIV-associated TB in clinical trials to understand and better manage the potential interactions between ART, CPT and the new TB agents.
HIV-associated TB in women and children
In high HIV-prevalence settings, more women are notified with TB compared with men, especially in the southern part of Africa, and this is due to the feminization of the HIV epidemic in this region [87]. There appears to be no difference in access, treatment or response to treatment between male and female patients. TB in pregnant women living with HIV increases the risk of vertical transmission of HIV and there is a higher risk of maternal mortality in pregnant women co-infected with HIV and TB compared with pregnant women who just have TB [87].
Although TB is not the great killer in HIV-infected children as it is in adults, it is nonetheless an important cause of their death [88,89]. Because of overlap in clinical features between children with HIV/AIDS and TB, accurate diagnosis of HIV-associated TB is very difficult, even with point scoring systems and diagnostic algorithms, which are anyway rarely used in routine practice [87]. In general, the HIV-TB strategies described for adults are equally applicable to children, but some brief comments are in order.
ART is recommended for all children under the age of two years with confirmed HIV infection, regardless of CD4 count [90], and under trial conditions, this is associated with a significant reduction in mortality and disease progression, including a reduction in the burden of active TB [91]. However, despite ART, the risk of TB remains high. Primary IPT in one trial in South Africa amongst children on ART failed to reduce this risk or the risk of death [92], while amongst young children not accessing ART, primary isoniazid prophylaxis in another South African trial was associated with reduced TB incidence and death [93]. The conundrum of how to best prevent TB in HIV-infected infants is still not resolved. Scale up of ART in this population is slow and requires far better access to early infant diagnosis and appropriate paediatric ART formulations. BCG vaccination in these children is potentially dangerous with an attendant risk of local and disseminated TB [89], underscoring the urgent need for a TB vaccine that can be safely given to young children with HIV infection.
TB case finding and diagnosis in children is hampered by the frequent failure to produce sputum and by a high proportion presenting with EPTB. Within these constraints, Xpert MTB/RIF is proving a potentially useful tool in children for the diagnosis of PTB (using induced sputum specimens) and EPTB [94], especially lymphadenitis [95].
Delivering HIV-TB services
Despite good progress made in HIV care and treatment for TB patients only one third of notified TB patients in 2010 were HIV tested, and of those, only 46% received ART [1]. Co-location and/or integration of TB and ART services are the key to achieving better and timely collaborative activities. In a South African township, for example, only 11% of HIV-infected patients with CD4 cell counts<50 cells/µL who were referred from TB services to separate HIV services started ART within four weeks of their TB diagnosis [96]. Centres for TB diagnosis and treatment and for HIV care and treatment must be integrated, located together or better matched quantitatively and geographically. HIV testing and TB treatment services are already well decentralized in many countries to peripheral sites, so the goal is now to decentralize services for TB diagnosis and ART provision. Innovative approaches are needed – for example, providing comprehensive HIV-TB care and treatment at the TB clinic for the duration of TB treatment with transfer to the HIV programme after TB treatment is completed [97]. Attention must be paid to clinic infrastructure with good natural cross-ventilation and patient-flow so as to minimize the risk of TB nosocomial transmission.
Current screening and treatment strategies miss large numbers of people who never make it to health facilities, so it is essential to think out of the box and determine whether community diagnostic, treatment and preventive services can be provided through home-based and mobile care teams. For example, in Malawi, oral self-testing for HIV was acceptable and accurate and has the potential for high uptake at community level if it can be supervised and linked to counselling and care [98]. In Zambia, household-based HIV and TB interventions offering HIV testing, easy access to TB diagnosis and linkage to HIV-TB care and treatment were feasible and reduced TB prevalence in the community [99101]. In Zimbabwe, active TB case finding in the community, particularly with a mobile van approach, was successful in detecting and reducing community prevalence of culture-positive TB [102]. In Thibela, South Africa, community-wide IPT for nine months regardless of HIV status in a gold-mining work force had no effect in reducing community-wide TB incidence or prevalence [103]. Moreover, any individual benefit in reducing TB risk among those who received IPT was limited to the duration of therapy [104], strengthening the argument for long-term therapy when used in countries with high TB transmission rates.
Not everyone identified and diagnosed through a community approach makes it to care, either for TB or HIV treatment [105], so it is essential that these gaps are plugged. As with case detection, integrated care and treatment can also be given through a home-based approach and may be associated with excellent treatment outcomes [106].
In summary, new scientific evidence shows us what interventions can make a difference and we have new tools to improve TB diagnosis. The job now is to apply this evidence and these new tools within routine healthcare systems and communities in resource-poor countries. Much earlier start of ART combined with IPT, active TB case finding using innovative TB diagnostic technology, quality assured HIV testing of patients with confirmed or suspected TB and timely initiation of CPT and ART to co-infected patients will save many lives and may be augmented by bold initiatives involving empirical TB treatment and community-based interventions. The 2012 World TB statement of “Zero TB deaths” fits well into the bold new vision articulated by UNAIDS of the Three Zeros – zero new HIV infections, zero discrimination and zero AIDS-related deaths [107]. Every year, HIV-associated TB robs 350,000 young men and women of a potentially long, healthy and productive life. As Bo Draser, Editor of the Transactions of the Royal Society of Tropical Medicine & Hygiene, once remarked “We need to take death away from these young people and make it the monopoly of the old” [108].
Acknowledgements
The views expressed in this article are those of the individual authors and do not necessarily reflect those of the institutions for which they work.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
ADH wrote the first draft. All authors participated in writing further drafts and reviewed and approved the final paper.
Funding sources
SDL is funded by the Wellcome Trust, London, UK.
1. World Health Organization. Geneva, Switzerland: WHO; 2011. Global tuberculosis control: WHO Report 2011. WHO/HTM/TB/2011.16.
2. World Health Organization. Epidemic update and health sector progress towards Universal Access. Geneva, Switzerland: World Health Organization; UNAIDS, UNICEF. Global HIV/AIDS Response. Progress Report 2011.
3. Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS. 2008;2:1897–908. [PMC free article] [PubMed]
4. Lucas SB, De Cock KM, Hounnou A, Peacock C, Diomande M, Honde M, et al. Contribution of tuberculosis to slim disease in Africa. BMJ. 1994;2:1531–3. [PMC free article] [PubMed]
5. Rana FS, Hawken MP, Mwachari C, Bhatt SM, Abdullah F, Ng'ang'a LW, et al. Autopsy study of HIV-1-positive and HIV-1-negative adult medical patients in Nairobi, Kenya. J Acquir Immune Defic Syndr. 2000;2:23–9. [PubMed]
6. Ansari NA, Kombe AH, Kenyon TA, Hone NM, Tappero JW, Nyirenda ST, et al. Pathology and causes of death in a group of 128 predominately HIV-positive patients in Botswana, 1997–1998. Int J Tuberc Lung Dis. 2002;2:55–63. [PubMed]
7. Cohen T, Murray M, Wallengren K, Alvarez GG, Samuel EY, Wilson D. The prevalence and drug sensitivity of tuberculosis among patients dying in hospital in KwaZulu-Natal, South Africa: a post-mortem study. PLoS Med. 2010;7:e1000296. [PMC free article] [PubMed]
8. Wong EB, Omar T, Setlhako G, Osih R, Murdoch D, Martinson N, et al. Causes of death in ART-treated adults: a post-mortem study from Johannesburg, South Africa. Abstracts of the XVIII International AIDS Conference, International AIDS Society; Vienna, Austria. 2010. Abstract WEPE0154.2010.
9. Harries AD, Hargreaves NJ, Gausi F, Kwanjana JH, Salaniponi FM. High early death rate in tuberculosis patients in Malawi. Int J Tuberc Lung Dis. 2001;2:1000–5. [PubMed]
10. Diul MY, Maher D, Harries AD. Tuberculosis case fatality rates in HIV prevalence populations in sub-Saharan Africa. AIDS. 2001;15:143–52. [PubMed]
11. Ackah AN, Coulibaly D, Digbeu H, Diallo K, Vetter KM, Coulibaly IM, et al. Response to treatment, mortality, and CD4 lymphocyte counts in HIV-infected persons with tuberculosis in Abidjan, Cote d'Ivoire. Lancet. 1995;2:607–10. [PubMed]
12. Perriens JH, St. Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. N Engl J Med. 1995;2:779–84. [PubMed]
13. Harries AD, Zachariah R, Corbett EL, Lawn SD, Santos-Filho ET, Chimzizi R, et al. The HIV-associated tuberculosis epidemic – when will we act? Lancet. 2010;2:1906–19. [PubMed]
14. World Health Organization. Guidelines for national programmes and other stakeholders. WHO/HTM/TB/2012.1 and WHO/HIV/2012.1 [Internet] Geneva, Switzerland: WHO; 2012. WHO policy on collaborative TB/HIV activities. [cited 2012 Mar 2]. Available from: http://whqlibdoc.who.int/publications/2012/9789241503006_eng.pdf.
15. World Health Organization Geneva: WHO; 2004. Interim policy on collaborative TB/HIV activities. WHO/HTM/TB/2004. 330. WHO/HTM/HIV/2004.1.
16. World Health Organization. Geneva, Switzerland: WHO; 2012. World Tuberculosis Day 2012: joint message from the Directors of WHO HIV and Stop TB Partnership.
17. Suthar AB, Lawn SD, del Amo J, Getahun H, Dye C, Sculier D, et al. Antiretroviral therapy for prevention of HIV-associated tuberculosis in developing countries: a systematic review and meta-analysis. PLoS Med. 2012;9:e1001270. [PMC free article] [PubMed]
18. Lawn SD, Harries AD, Williams BG, Chaisson RE, Losina E, De Cock KM, et al. Antiretroviral therapy and the control of HIV-associated tuberculosis. Will ART do it? Int J Tuberc Lung Dis. 2011;2:571–81. [PubMed]
19. Gupta A, Wood R, Kaplan R, Bekker L-G, Lawn SD. Tuberculosis incidence rates during 8 years of follow-up of an antiretroviral treatment cohort in South Africa: comparison with rates in the community. PLoS One. 2012;7:e34156. [PMC free article] [PubMed]
20. Zachariah R, Bemelmans M, Akesson A, Gomani P, Phiri K, Isake B, et al. Reduced tuberculosis case notification associated with scaling up antiretroviral treatment in rural Malawi. Int J Tuberc Lung Dis. 2011;2:933–7. [PubMed]
21. Middelkoop K, Bekker L-G, Myer L, Johnson LF, Kloos M, Morrow C, et al. Antiretroviral therapy and TB notification rates in a high HIV prevalence South African community. J Acquir Immune Defic Syndr. 2011;2:263–9. [PMC free article] [PubMed]
22. Severe P, Juste MAJ, Ambroise A, Eliacin L, Marchand C, Apollon S, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010;2:257–65. [PMC free article] [PubMed]
23. World Health Organization. Recommendations for a public health approach. Geneva, Switzerland: WHO; 2010. Antiretroviral therapy for HIV infection in adults and adolescents. 2010 Revision. [PubMed]
24. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. for the HPTN 052 Study Team Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;2:493–505. [PMC free article] [PubMed]
25. Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009;373:48–57. [PubMed]
26. Williams BG, Granich R, De Cock KM, Glaziou P, Sharma A, Dye C. Antiretroviral therapy for tuberculosis control in nine African countries. Proc Nat Acad Sci U S A. 2010;2:19485–9. [PubMed]
27. Granich R, Gupta S, Suthar AB, Smyth C, Hoos D, Vitoria M, et al. on behalf of the ART in Prevention of HIV and TB Research Writing Group Antiretroviral therapy in prevention of HIV and TB: update on current research efforts. Curr HIV Res. 2011;2:446–69. [PMC free article] [PubMed]
28. Schouten EJ, Jahn A, Midiani D, Makombe SD, Mnthambala A, Chirwa Z, et al. Prevention of mother-to-child transmission of HIV and the health-related Millennium Development Goals: time for a public health approach. Lancet. 2011;2:282–4. [PubMed]
29. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV-infected persons. Cochrane Database Syst Rev. 2010:CD000171. [PubMed]
30. WHO. UNAIDS. Policy statement on preventive therapy against tuberculosis in people living with HIV [Internet] WHO/TB/98.255. UNAIDS/98.34. Geneva, Switzerland: WHO; 1998 [cited 2012 Mar 30]. Available from: http://whqlibdoc.who.int/hq/1998/WHO_TB_98.255.pdf.
31. World Health Organization. Geneva, Switzerland: WHO; 2011. Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings [Internet] [cited 2012 July 15]. Available from: http://whqlibdoc.who.int/pubblications/2011/9789241500708_eng.pdf.
32. Samandari T, Agizew TB, Nyirenda S, Tedla Z, Sibanda T, Shang N, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;2:1588–98. [PubMed]
33. Samandari T, Agizew T, Nyirenda S, Tedla Z, Sibanda T, Mosimaneotsile B, et al. TB incidence increase after cessation of 36 months isoniazid prophylaxis in HIV+ adults: Botswana. 19th Conference on Retroviruses and Opportunistic Infections 2012, Session 41, Oral Abstracts, Number #147.
34. Golub JE, Saraceni V, Cavalcante SC, Pacheco AG, Moulton LH, King BG, 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;2:1441–8. [PMC free article] [PubMed]
35. Golub JE, Pronyk P, Mohapi L, Thsabangu N, Moshabela M, Struthers H, et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS. 2009;2:631–6. [PMC free article] [PubMed]
36. Lawn SD, Wood R, De Cock KM, Kranzer K, Lewis JJ, Churchyard GJ. Antiretrovirals and isoniazid preventive therapy in the prevention of HIV-associated tuberculosis in settings with limited-health-care resources. Lancet Infect Dis. 2010;2:489–98. [PubMed]
37. Getahun H, Kittikraisak W, Heilig CM, Corbett EL, Ayles H, Cain KP, et al. Development of a standardised screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies. PLoS Med. 2011;8:e1000391. [PMC free article] [PubMed]
38. WHO, UNAIDS. WHO/HTM/TB/2009.414. WHO/HTM/HIV/09.01. Geneva, Switzerland: World Health Organization; 2009. A guide to monitoring and evaluation for collaborative TB/HIV activities.
39. Gupta A, Chandrasekhar A, Gupte N, Patil S, Bhosale R, Sambarey P, et al. the Medical College-Johns Hopkins University Study Group Symptom screening among HIV-infected pregnant women is acceptable and has high negative predictive value for active tuberculosis. Clin Infect Dis. 2011;2:1015–8. [PMC free article] [PubMed]
40. Kranzer K, Houben RMGJ, Bekker LG, Wood R, Lawn SD. Yield of HIV-associated tuberculosis during intensified case finding in resource-limited settings: a systematic review and meta-analysis. Lancet Infect Dis. 2010;2:93–102. [PMC free article] [PubMed]
41. Oni T, Burke R, Tsekela R, Bangani N, Seldon R, Gideon HP, et al. High prevalence of subclinical tuberculosis in HIV-1-infected persons without advanced immunodeficiency: implications for TB screening. Thorax. 2011;2:669–73. [PMC free article] [PubMed]
42. Lawn SD, Kerkhoff AD, Wood R. Progression of subclinical culture-positive tuberculosis to symptomatic disease in HIV-infected individuals. AIDS. 2011;2:2190–1. [PubMed]
43. Reid MJA, Shah NS. Approaches to tuberculosis screening and diagnosis in people with HIV in resource-limited settings. Lancet Infect Dis. 2009;2:173–84. [PubMed]
44. Lawn SD, Wood R. Tuberculosis in antiretroviral treatment services in resource-limited settings: addressing the challenges of screening and diagnosis. J Infect Dis. 2011;204:S1159–67. [PMC free article] [PubMed]
45. Chamie G, Luetkemeyer A, Walusimbi-Nanteza M, Okwera A, Whalen CC, Mugerwa RD, et al. Significant variation in presentation of pulmonary tuberculosis across a high resolution of CD4 strata. Int J Tuberc Lung Dis. 2010;2:1295–302. [PMC free article] [PubMed]
46. Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010;2:1005–15. [PMC free article] [PubMed]
47. Lawn SD, Zumla AI. Diagnosis of extrapulmonary tuberculosis using the Xpert MTB/RIF assay. Exp Rev Anti-Infect Ther. 2012;2:631–5. [PMC free article] [PubMed]
48. Boehme CC, Nicol MP, Nabeta P, Michael JS, Gotuzzo E, Tahirli R, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet. 2011;2:1495–505. [PMC free article] [PubMed]
49. Lawn SD, Kerkhoff AD, Wood R. Location of Xpert MTB/RIF in centralised laboratories in South Africa undermines potential impact. Int J Tuberc Lung Dis. 2012;2:701. [PubMed]
50. Lawn SD, Kerkhoff AD, Vogt M, Wood R. Diagnostic accuracy of a low-cost, urine antigen, point-of-care screening assay for HIV-associated pulmonary tuberculosis before antiretroviral therapy: a descriptive study. Lancet Infect Dis. 2012;12:201–9. [PMC free article] [PubMed]
51. Dorman S, Manabe Y, Nicol M, Nakiyingi L, Moodley M, Zemanay W, et al. Accuracy of determine TB-LAM lateral flow test for diagnosis of TB in HIV+ adults: interim results from a multicenter study. 19th Conference on Retroviruses and Opportunistic Infections 2012, Session 41, Oral Abstracts, Number #149 aLB.
52. Lawn SD, Ayles H, Egwaga S, Williams B, Mukadi YD, Santos-Filho ED, et al. Potential utility of empirical tuberculosis treatment for HIV-infected patients with advanced immunodeficiency in high TB-HIV burden settings. Int J Tuberc Lung Dis. 2011;2:287–95. [PubMed]
53. World Health Organization. Guidelines on co-trimoxazole prophylaxis for HIV-related among children, adolescents and adults. Recommendations for a public health approach [Internet]. Geneva, Switzerland: WHO; 2006 [cited 2010 Feb 6]. Available from: http://www.who.int/hiv/pub/guidelines/ctx/en/index.html.
54. Wiktor SZ, Sassan-Morokro M, Grant AD, Abouya L, Karon JM, Maurice C, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-infected patients with tuberculosis in Abidjan, Cote d'Ivoire: a randomised controlled trial. Lancet. 1999;2:1469–74. [PubMed]
55. Nunn AJ, Mwaba P, Chintu C, Mwinga A, Darbyshire JH, Zumla A., for the UNZA-UCLMS Project LUCOT Collaboration Role of co-trimoxazole prophylaxis in reducing mortality in HIV infected adults being treated for tuberculosis: randomized clinical trial. BMJ. 2008;337:a257. doi: 10.1136/bmj.a257. (1-7) [PMC free article] [PubMed] [Cross Ref]
56. Zachariah R, Spielmann M-P, Chinji C, Gomani P, Arendt V, Hargreaves NJ, et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole reduces mortality in tuberculosis patients in Thyolo, Malawi. AIDS. 2003;2:1053–61. [PubMed]
57. Mwaungulu FBD, Floyd S, Crampin AC, Kasimba S, Malema S, Kanyongoloka H, et al. Cotrimoxazole prophylaxis reduces mortality in human immunodeficiency virus-positive tuberculosis patients in Karonga district, Malawi. Bull World Health Organ. 2004;2:354–62. [PubMed]
58. Grimwade K, Sturm W, Nunn AJ, Mbatha D, Zungu D, Gilks CF. Effectiveness of cotrimoxazole on mortality in adults with tuberculosis in rural South Africa. AIDS. 2005;2:163–8. [PubMed]
59. Lowrance D, Makombe S, Harries A, Yu J, Aberle-Grasse J, Eiger O, et al. Lower early mortality rates among patients receiving antiretroviral treatment at clinics offering cotrimoxazole prophylaxis in Malawi. J Acquir Immune Defic Syndr. 2007;2:56–61. [PubMed]
60. Walker AS, Ford D, Gilks CF, Munderi P, Ssali F, Reid A, et al. Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort. Lancet. 2010;2:1278–86. [PMC free article] [PubMed]
61. Suthar AB, Granich R, Mermin J, Van Rie A. Effect of cotrimoxazole on mortality in HIV-infected adults on antiretroviral therapy: a systematic review and meta-analysis. Bull World Health Organ. 2012;2:128–38C. [PubMed]
62. 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;2:1605–12. [PubMed]
63. Lawn SD, Kranzer K, Wood R. Antiretroviral therapy for control of the HIV-associated tuberculosis epidemic in resource-limited settings. Clin Chest Med. 2009;2:685–99. [PMC free article] [PubMed]
64. Khan FA, Minion J, Pai M, Royce S, Burman W, Harries AD, et al. Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis. Clin Infect Dis. 2010;2:1288–99. [PubMed]
65. WHO, UNAIDS. Geneva, Switzerland: WHO; 2007. Guidance on provider-initiated HIV testing and counseling in health facilities.
66. Odhiambo J, Kizitu W, Njoroge A, Wambua N, Nganga L, Mburu M, et al. Provider initiated HIV testing and counselling for TB patients and suspects in Nairobi, Kenya. Int J Tuberc Lung Dis. 2008;12(Suppl 1):S63–8. [PubMed]
67. Harries AD, Zachariah R, Lawn SD. Providing HIV care for co-infected tuberculosis patients: a perspective from sub-Saharan Africa (State of the ART) Int J Tuberc Lung Dis. 2009;13:6–16. [PubMed]
68. Kyeyune R, den Boon S, Cattamanchi A, Davis JL, Worodria W, Yoo SD, et al. Causes of early mortality in HIV-infected TB suspects in an East African Referral Hospital. J Acquir Immune Defic Syndr. 2010;2:446–50. [PMC free article] [PubMed]
69. Porskrog A, Bjerregaard-Andersen M, Oliveira I, Joaquim LC, Camara C, Andersen PL, et al. Enhanced tuberculosis identification through 1-month follow-up of smear-negative tuberculosis suspects. Int J Tuberc Lung Dis. 2011;2:459–64. [PubMed]
70. Dimairo M, MacPherson P, Bandason T, Zezai A, Munyati SS, Butterworth AE, et al. The risk and timing of tuberculosis diagnosed in smear-negative TB suspects: a 12 month cohort study in Harare, Zimbabwe. PLoS One. 2010;5:e11849. [PMC free article] [PubMed]
71. MacPherson P, Dimairo M, Bandason T, Zezai A, Munyati SS, Butterworth AE, et al. Risk factors for mortality in smear-negative tuberculosis suspects: a cohort study in Harare, Zimbabwe. Int J Tuberc Lung Dis. 2011;2:1390–6. [PMC free article] [PubMed]
72. Karim SSA, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010;2:697–706. [PMC free article] [PubMed]
73. Blanc FX, Sok T, Laureillard D, Borand L, Rekacewicz C, Nerrienet E, et al. for the CAMELIA (ANRS 1295-CIPRA KH001) Study Team Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;2:1471–81. [PubMed]
74. Havlir DV, Kendall MA, Ive P, Kumwenda J, Swindells S, Qasba SS, et al. for the AIDS Clinical Trials Group Study A5221 Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;2:1482–91. [PMC free article] [PubMed]
75. Karim SSA, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;2:1492–501. [PMC free article] [PubMed]
76. Degu WA, Lindquist L, Aderaye G, Aklillu E, Wold AH, Ali GY, et al. Randomized clinical trial to determine efficacy and safety of ART 1 week after TB therapy in patients with CD4 counts<200 cells/µL. 19th Conference on Retroviruses and Opportunistic Infections 2012, Session 41, Oral Abstracts, Number #144.
77. Luetkemeyer A, Kendall M, Nyirenda M, Wu X, Ive P, Andersen J, et al. A5221 Study Team Severity and timing of paradoxical TB-IRIS in a 48-week multicenter randomized trial of immediate vs early ART in patients with CD4<250 cells/µL starting TB Treatment: A5221 STRIDE Study. 19th Conference on Retroviruses and Opportunistic Infections 2012, Session 41, Oral Abstracts, Number #145.
78. Torok ME, Yen NT, Chau TT, Mai NT, Phu NH, Mai PP, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)-associated tuberculous meningitis. Clin Infect Dis. 2011;2:1374–83. [PubMed]
79. Loeliger A, Suthar AB, Ripin D, Glaziou P, O'Brien M, Renaud-Thery F, et al. Protease inhibitor-containing antiretroviral treatment and tuberculosis: can rifabutin fill the breach? Int J Tuberc Lung Dis. 2012;2:6–15. [PubMed]
80. Wells CD, Cegielski JP, Nelson LJ, Lasrerson KF, Holtz TH, Finlay A, et al. HIV infection and multidrug-resistant tuberculosis – the perfect storm. J Infect Dis. 2007;196:S86–107. [PubMed]
81. Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Laloo U, 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;2:1575–80. [PubMed]
82. Gandhi NR, Shah NS, Andrews JR, Vella V, Moll AP, Scott M, et al. Tugela Ferry Care and Research (TF_CARES) Collaboration. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med. 2010;2:80–6. [PubMed]
83. Palacios E, Franke M, Munoz M, Hurtado R, Dallman R, Chalco K, et al. HIV-positive patients treated for multidrug-resistant tuberculosis: clinical outcomes in the HAART era. Int J Tuberc Lung Dis. 2012;2:348–54. [PubMed]
84. Dheda K, Shean K, Zumla A, Badri M, Streicher EM, Page-Shipp L, et al. Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study. Lancet. 2010;2:1798–807. [PubMed]
85. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis; 2011 Update; Geneva, Switzerland: WHO; 2011. WHO/HTM/TB/2011.6. [PubMed]
86. Scano F, Vitoria M, Burman W, Harries AD, Gilks CF, Havlir D. Management of HIV-infected patients with MDR- and XDR-TB in resource-limited settings. Int J Tuberc Lung Dis. 2008;2:1370–5. [PubMed]
87. Getahun H, Sculier D, Sismanidis C, Grzemska M, Raviglione M. Prevention, diagnosis, and treatment of tuberculosis in children and mothers: evidence for action for maternal, neonatal, and child health services. J Infect Dis. 2012;S205(Suppl 2):S16–27. [PubMed]
88. Chintu C, Mudenda V, Lucas S, Nunn A, Lishimpi K, Maswahu D, et al. UNZA-UCLMS Project Paediatric Post-mortem Study Group. Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study. Lancet. 2002;2:985–90. [PubMed]
89. Ansari NA, Kombe AH, Kenyon TA, Mazhani L, Binkin N, Tappero JW, et al. Pathology and causes of death in a series of human immunodeficiency virus-positive and -negative pediatric referral hospital admissions in Botswana. Pediatr Infect Dis J. 2003;2:43–7. [PubMed]
90. World Health Organization. Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach; Geneva, Switzerland: WHO; 2010. Revision. [PubMed]
91. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. for the CHER Study Team Early antiretroviral therapy and mortality among HIV-infected infants. N Eng J Med. 2008;2:2233–44. [PMC free article] [PubMed]
92. Madhi SA, Nachman S, Violari A, Kim S, Cotton MF, Bobat R, et al. for the P1041 Study Team Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Eng J Med. 2011;2:21–31. [PMC free article] [PubMed]
93. Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007;2:136. [PMC free article] [PubMed]
94. Nicol MP, Workman L, Isaacs W, Munro J, Black F, Eley B, et al. Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town, South Africa: a descriptive study. Lancet Infect Dis. 2011;2:819–24. [PubMed]
95. Ligthelm LJ, Nicol MP, Hoek KG, Jacobson R, van Helden PD, Marais BJ, et al. Xpert MTB/RIF for rapid diagnosis of tuberculosis lymphadenitis from fine-needle-aspiration biopsy specimens. J Clin Microbiol. 2011;2:3967–70. [PMC free article] [PubMed]
96. Lawn SD, Wood R. Timing of antiretroviral therapy for HIV-1-associated tuberculosis. N Engl J Med. 2012;2:474. [PubMed]
97. Howard AA, El-Sadr WM. Integration of tuberculosis and HIV services in sub-Saharan Africa: lessons learned. Clin Infect Dis. 2010;50(S3):S238–44. [PubMed]
98. Choko AT, Desmond N, Webb EL, Chavula K, Napierala-Mavedzenge S, Gaydos CA, et al. The uptake and accuracy of oral kits for HIV self-testing in high HIV prevalence setting: a cross-sectional feasibility study in Blantyre, Malawi. PLoS Med. 2011;8:e1001102. [PMC free article] [PubMed]
99. Smart T. An intensive household counselling intervention reduces the burden of TB in ZAMSTAR study. HIV and AIDS Treatment in Practice. 2011;(184):3–4.
100. Smart T. The implications of ZAMSTAR for research and policy. HIV and AIDS Treatment in Practice. 2011;(184):5–8.
101. Ayles H., the ZAMSTAR Study Team A household-based HIV and TB intervention increases HIV testing in households and reduces prevalence of TB at the community level: The ZAMSTAR Community Randomized Trial. 19th Conference on Retroviruses and Opportunistic Infections 2012, Session 41, Oral Abstracts, Number #149 bLB.
102. Corbett EL, Bandason T, Duong T, Dauya B, Makamure B, Churchyard GJ, et al. Comparison of two active case-finding strategies for community-based diagnosis of symptomatic smear-positive tuberculosis and control of infectious tuberculosis in Harare, Zimbabwe (DETECTB): a cluster-randomised trial. Lancet. 2010;2:1244–53. [PMC free article] [PubMed]
103. Churchyard G, Fielding K, Lewis J, Coetzee L, Corbett E, Godfrey-Faussett P, et al. on behalf of the Thibela TB Team Community-wide isoniazid preventive therapy does not improve TB control among gold miners: the Thibela TB Study, South Africa. 19th Conference on Retroviruses and Opportunistic Infections 2012, Session 41, Oral Abstracts, Number #150aLB.
104. Fielding K, Grant A, Lewis J, Hayes R, Churchyard G. Individual-level effect of isoniazid preventive therapy on risk of TB: The Thibela TB study. 19th Conference on Retroviruses and Opportunistic Infections 2012, Session 41, Oral Abstracts, Number #150bLB.
105. Kranzer K, Lawn SD, Meyer-Rath G, Vassall A, Raditlhalo E, Govindasamy D, et al. Feasibility, yield and cost of active tuberculosis case finding linked to a mobile HIV testing service in Cape Town, South Africa. Tuberculosis control in a South African community with high HIV prevalence: the role of intensified case-finding and antiretroviral therapy. PLoS Med. 2012 Forthcoming. [PMC free article] [PubMed]
106. Gandhi N, Moll AP, Lalloo U, Pawinski R, Zeller K, Moodley P, et al. on behalf of the Tugela Ferry Care and Research (TFCaRes) Collaboration Successful integration of tuberculosis and HIV treatment in rural South Africa: The Sizonq'oba Study. J Acquir Immune Defic Syndr. 2009;2:37–43. [PubMed]
107. UNAIDS. 2010 World AIDS Day Message. Zero new HIV infections. Zero discrimination; Zero AIDS-related deaths; 2010. Dec 1,
108. Drasar B. Editorial. Int Health. 2009;1:1–2. [PubMed]
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