By the end of 2013, there were an estimated 35 million people living with HIV (PLHIV) globally, 70% of whom were living in sub-Saharan Africa.1 The risk of developing tuberculosis (TB) among PLHIV is 20–37 times higher compared with HIV-uninfected people.2 A recent systematic review of yield of HIV-associated TB during intensified TB case finding (ICF) in resource-limited settings showed a median prevalence of TB disease of 8% among PLHIV attending HIV care and treatment clinics, with a range of up to 25% in some of these clinics.3 The median TB prevalence among HIV-infected clients attending maternal and child health clinics in the same review was also high (range, 2.1%–3.5%).3 In 2013, 1.1 million of 9.0 million people (13%) who developed TB were HIV infected and 360,000 deaths from HIV-associated TB accounted for approximately a quarter of all HIV-associated deaths.2
Despite being a preventable and curable disease, TB remains the leading cause of morbidity and mortality among PLHIV.4,5 Without antiretroviral treatment (ART), up to 50% of PLHIV who are diagnosed with TB die during the first 6–8 months of TB treatment.6–8 Among PLHIV with multidrug or extensively drug-resistant TB, the mortality risk is much higher reaching 72%–98%.9,10 Studies of PLHIV in sub-Saharan Africa have also documented high rates of TB among PLHIV initiating ART; however, TB frequently remains undiagnosed.11,12 Recent autopsy studies among PLHIV without known TB disease have demonstrated high TB rates (21%–52%), even after receiving ART for 3–10 months.13–15 Although ART is known to reduce the risk of TB among PLHIV cohorts by a mean of 67% (95% confidence interval: 61% to 73%),16 the rate of TB among PLHIV with sustained high CD4 counts on ART for longer than 5 years remains more than 4 times the rate of TB in HIV-uninfected individuals.17
If not adequately addressed, TB has the potential to undermine the great strides made globally in rapidly expanding HIV care and treatment. Early detection and treatment of TB disease among PLHIV are critical components of comprehensive HIV care, and this includes TB screening at every clinical encounter. Given the extensive published evidence demonstrating the morbidity and mortality among PLHIV with TB disease and existing global recommendations and strong guidance under the US President's Emergency Plan for AIDS Relief (PEPFAR) regarding the need for TB screening among PLHIV, an additional evidence review to assess the impact of TB screening among PLHIV on the 5 outcomes of interest (mortality, morbidity, retention in HIV care, quality of life, and reduction of HIV transmission) was not undertaken as part of the larger review of 12 care and support interventions for PLHIV presented in this supplement.18 Therefore, in this article, we summarize the available evidence and recommendations for TB screening as part of routine care for PLHIV in resource-limited settings.
GLOBAL RECOMMENDATIONS AND PEPFAR GUIDANCE
The World Health Organization (WHO) recommends implementation of the 3 I's [ICF, isoniazid preventive therapy (IPT), and TB infection control (TBIC)], along with early initiation of ART, as core strategies for reducing HIV-associated TB. Since the release of its interim policy for TB/HIV collaborative activities in 2004, WHO has consistently advocated for regular TB screening among PLHIV as the first step of TB ICF.19 The WHO Policy on TB/HIV Collaborative Activities and Guidelines for Intensified Tuberculosis Case-Finding and Isoniazid Preventive Therapy for People Living With HIV in Resource Constrained Settings recommend that all PLHIV including children, adults, and pregnant women be regularly screened for TB as a routine component of every clinical visit using an evidence-based clinical algorithm (current cough, fever, weight loss, or night sweats) and that PLHIV with presumptive TB (ie, persons with at least one of these symptoms) should be further evaluated for TB disease and initiated on TB treatment if diagnosed with TB disease.20,21 The 4-symptom screening tool recommended by WHO was derived from a meta-analysis of 12 studies that included approximately 10,000 PLHIV, among whom 5.8% had TB disease. This meta-analysis showed that the 4-symptom screen tool had a sensitivity of 78.9%, thus identifying the majority of PLHIV with presumptive TB who needed further diagnostic evaluation.22
These recommendations have been further emphasized in international HIV guidance, including the 2013 WHO Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV infection.23 The PEPFAR Blueprint describes the US Government's approach to creating an AIDS-free generation and calls for improving the survival of PLHIV by reducing HIV-associated morbidity and mortality through smart investments in tackling HIV-associated TB.24 PEPFAR additionally provides technical guidance highlighting the need to include TB screening for HIV-infected children and adults, including pregnant women,25 in program planning and monitoring and evaluation efforts.
TB Screening and the ICF Clinical Cascade
Despite global recommendations, implementation of universal and routine TB screening remains sub-optimal. Uptake of TB screening varies widely. A study from Mozambique showed that 61% of PLHIV overall had documentation of TB screening in their records, but this varied from 2% to 98% across the multiple sites assessed in the study.26
Once PLHIV are screened for TB, those identified as having presumptive TB need to undergo TB diagnostic evaluation. However, this continues to be a large gap in the ICF clinical cascade. A study from Kenya found that fewer than 15% of PLHIV with symptoms suggestive of TB disease received any form of diagnostic evaluation.27 Lapses in diagnostic evaluation are multifactorial and may be because of a lack of referral by a provider or failure to complete recommended evaluations by the patient, which may be influenced by transportation costs or costs of the diagnostic test itself.28 Systematic follow-up of PLHIV with presumptive TB through the use of monitoring and evaluation tools, such as a presumptive TB register, is needed to reduce loss to follow-up and increase TB case detection and treatment rates. Incorporating TB screening and diagnostic cascade variables into the HIV recording and reporting system would be a critical step in ensuring appropriate TB diagnostic evaluation and subsequent treatment initiation if needed. Where electronic recording and reporting systems exist, establishing linkages between medical record systems in HIV clinics, TB clinics, and laboratories will also minimize loss to follow-up, especially in settings where a national unique identifier is available.
Despite evidence demonstrating the poor performance of smear microscopy for TB diagnosis among PLHIV,29,30 this remains the main diagnostic tool for TB in many resource-limited settings.2 The paucibacillary nature of pulmonary disease among PLHIV typically yields negative sputum smear results, thus limiting its utility.31 The new, fully automated polymerase chain reaction–based Xpert MTB/RIF assay can provide bacteriological confirmation of TB disease and identify rifampin resistance in less than 2 hours. Among PLHIV, Xpert MTB/RIF has a sensitivity of 76% compared with sputum culture in liquid or solid media32 and offers great potential to revolutionize TB diagnosis for this high-risk population. WHO recommends that Xpert MTB/RIF should be used rather than conventional microscopy as the initial diagnostic test for all persons with suspected multidrug TB or HIV-associated TB.33 By the end of June 2014, 3269 Xpert MTB/RIF machines had been procured in the public sector. Proper placement of these machines in high HIV prevalence areas and a seamless sample transport network for specimens and results return between clinical sites and laboratories is critical to realize the impact of Xpert MTB/RIF for improving TB case finding among PLHIV. There is limited evidence of the impact of rapid diagnostics such as Xpert MTB/RIF on morbidity and mortality among PLHIV. Results from a recent randomized trial comparing Xpert MTB/RIF with smear microscopy in a peripheral health center in South Africa demonstrated that Xpert MTB/RIF significantly increased same-day treatment initiation, but it yielded no difference in validated measures of morbidity; this study was not powered to measure mortality and additional research is needed.34
TB Screening and Implementation of Other TB/HIV Interventions
In addition to being the critical first step to ICF, TB screening is the gateway to implementation of other important TB/HIV interventions, including IPT, TBIC, and ART. WHO recommends that all HIV-infected children aged 1 year or older and adults living with HIV without TB disease receive at least 6 months of IPT. The evidence for the impact of IPT on morbidity and mortality for PLHIV is reviewed in another article in this supplement.35 TB screening with WHO's 4-symptom screening tool has a negative predictive value of 97.7%, making this a useful tool for identifying PLHIV who are unlikely to have TB and who are eligible for IPT.22
Undiagnosed TB disease among PLHIV attending HIV care and treatment services poses a serious TBIC challenge.36 Considering the high susceptibility of PLHIV to TB disease, there is a potential for nosocomial transmission of Mycobacterium tuberculosis in these settings if TBIC procedures are not strictly followed. The risk is particularly high among PLHIV newly enrolling in HIV care who have a high prevalence of undiagnosed TB and who often spend significant time in the overcrowded health facilities. Nosocomial transmission might have played a critical role in the 2006 outbreak of extensively drug-resistant TB among patients accessing ART in rural KwaZulu-Natal, South Africa.9 Finding symptomatic patients through TB screening is the first step in the implementation of other administrative TBIC measures, including separation and fast tracking of PLHIV with presumptive TB, to prevent the spread of TB. Screening and rapid diagnosis leading to early initiation of TB treatment are central to reducing the infectious period and the risk of TB transmission.
Finally, TB screening and TB ICF are instrumental in finding PLHIV with TB disease who are automatically eligible for ART regardless of CD4 count according to the 2013 WHO Consolidated Guidelines.23 TB screening should therefore be considered as a tool for identifying those with TB disease who are thus eligible for ART.
Since publication of the WHO Guidelines for Intensified Tuberculosis Case-Finding and Isoniazid Preventive Therapy for People Living With HIV in Resource Constrained Settings, multiple evaluations have been conducted to assess the performance of TB screening using WHO's 4-symptom screening algorithm. Several studies suggest that the WHO screening tool performs better for newly enrolling PLHIV and that the sensitivity of this tool among PLHIV already receiving ART, HIV-infected pregnant women, and PLHIV who have previously been screened for TB is lower compared with what was reported in the meta-analysis.37–39 Although ongoing TB screening should continue using the WHO recommended tool at each visit, more research is needed to determine the optimal frequency of TB screening and the best methods for repeat TB screening and for screening HIV-infected pregnant women.
Among the general PLHIV population, symptom screening detects the majority of TB cases; however, evidence shows that a 15%–25% of PLHIV with bacteriologically confirmed TB disease might be asymptomatic. Considering the high prevalence of TB among PLHIV in many sub-Saharan African countries and the likelihood of missing asymptomatic TB cases using the clinical screening algorithm, Xpert MTB/RIF may have a role as a screening tool for all newly enrolling PLHIV. Although screening with Xpert MTB/RIF requires an up-front cost that symptom-based screening does not, this strategy may more reliably find PLHIV with TB disease who need both TB treatment and ART. The cost-effectiveness of this approach however needs to be evaluated.
WHO recommends that national HIV programs take ownership of the 3Is for TB/HIV. Although TB screening is usually conducted at HIV care and treatment clinics, in most instances PLHIV with presumptive TB are referred to the TB clinic for further diagnostic evaluation. However, this remains the most “leaky” step in the clinical cascade for TB evaluation.27 Better communication between the HIV and TB programs and the laboratory staff including interconnectivity of their information systems will be instrumental in closing this gap in the ICF clinical cascade. Providing TB and HIV services through integrated TB/HIV clinics could also minimize the need for referral of patients between clinical programs and has great potential to improve patient care.
TB disease continues to be the leading cause of morbidity and mortality among PLHIV, and prevention and treatment of HIV-associated TB are critical to improve the survival of PLHIV. TB screening among PLHIV is the basis for implementation of the key TB/HIV interventions that reduce TB-associated mortality among PLHIV, including ICF, IPT, TBIC, and appropriate initiation of TB treatment and ART among PLHIV with TB. HIV programs must work to close the gaps in the TB ICF clinical cascade and ensure that regular and consistent TB screening is an integral part of routine clinical services for PLHIV at each clinic visit.
1. Joint United Nations Programme on HIV
/AIDS (UNAIDS). The Gap Report. Geneva, Switzerland: UNAIDS; 2014.
2. World Health Organization. Global TB Report 2014. WHO/HTM/TB/2014.08. Geneva, Switzerland: WHO; 2014.
3. Kranzer K, Houben R, Glynn J, et al.. Yield of HIV
during intensified case finding in resource-limited settings: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10:93–102.
4. Lawn SD, Kranzer K, Wood R. Antiretroviral therapy for control of the HIV
epidemic in resource-limited settings. Clin Chest Med. 2009;30:685–699.
5. Golub JE, Durovni B, King BS, et al.. Recurrent tuberculosis
-infected patients in Rio de Janeiro, Brazil. AIDS. 2008;22:2527–2533.
6. Mukadi YD, Wiktor SZ, Coulibaly IM, et al.. Impact of HIV
infection on the development, clinical presentation, and outcome of tuberculosis
among children in Abidjan, Cote d'Ivoire. AIDS. 1997;11:1151–1158.
7. Manosuthi W, Chottanapand S, Thongyen S, et al.. Survival rate and risk factors of mortality among HIV
-coinfected patients with and without antiretroviral therapy. J Acquir Immune Defic Syndr. 2006;43:42–46.
8. Lawn SD, Myer L, Orrell C, et al.. Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design. AIDS 2005;19:2141–2148.
9. Gandhi NR, Moll A, Sturm AW, et al.. Extensively drug-resistant tuberculosis
as a cause of death in patients co-infected with tuberculosis
in a rural area of South Africa. Lancet. 2006;368:1575–1580.
10. 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.
11. Lawn SD, Kranzer K, Edwards DJ, et al.. Tuberculosis
during the first year of antiretroviral therapy in a South African cohort using an intensive pretreatment screening strategy. AIDS. 2010;24:1323–1328.
12. 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.
13. Neil M, Omar T, Rakgokong M, et al.. Undiagnosed infectious TB in adult home deaths: South Africa. Session 145; poster 837. Proceedings of the 20th conference on retrovirus and opportunistic infections. March 3-6, 2013, Atlanta, GA.
14. Some F, Gardner A, Mwangi A, et al.. The burden of TB among patients dying with HIV
/AIDS while on ART: Western Kenya. Proceedings of the 20th conference on retrovirus and opportunistic infections. Session 145; poster 831. Proceedings of the 20th conference on retrovirus and opportunistic infections. March 3-6, 2013, Atlanta, GA.
15. Mutevedzi P, Lessells R, Newell M. Early mortality following initiation of ART in rural South Africa: the contribution of existing co-morbidities. Session 145; poster 832. Proceedings of the 20th conference on retrovirus and opportunistic infections. March 3-6, 2013, Atlanta, GA.
16. Lawn S, Wood R, DeCock K, et al.. Antiretrovirals and isoniazid preventive therapy in the prevention of HIV
in settings with limited health-care resources. Lancet Infect Dis. 2010;10:489–498.
17. Gupta A, Wood R, Kaplan R, et al.. 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.
18. Kaplan JE, Hamm TE, Forhan S, et al.. The impact of HIV
care and support interventions on key outcomes in low and middle-income countries: a literature review–introduction. J Acquir Immune Defic Syndr. 2015;68(suppl 3):S253–S256.
19. World Health Organization. Interim Policy on Collaborative TB/HIV
Activities. Guidelines for National Programs and Other Stakeholders. WHO/HTM/TB/2004.330. Geneva, Switzerland: WHO; 2004.
20. World Health Organization. WHO Policy on Collaborative TB/HIV
Activities. Guidelines for National Programs and Other Stakeholders. WHO/HTM/TB/2012.1. Geneva, Switzerland: WHO; 2012.
21. World Health Organization. Guidelines for Intensified Tuberculosis
Case-Finding and Isoniazid Preventive Therapy for People Living with HIV
in Resource Constrained Settings. Geneva, Switzerland: WHO; 2010.
22. Getahun H, Kittikraisak J, Heilig C, et al.. Development of a standardized screening rule for tuberculosis
in people living with HIV
in resource-limited settings: individual data meta-analysis of observational studies. PLoS Med. 8:e1000391. doi: 10.1371/journal.pmed.1000391.
23. World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV
Infection. Geneva, Switzerland: WHO; 2013.
25. US President's Plan for AIDS Relief. PMTCT/Pediatric HIV
technical working group recommendations for integration of tuberculosis
screening into PMTCT/Pediatric HIV
programs. 2012. Available at: http://www.pepfar.gov/documents/organization/194952.pdf
. Accessed December 11, 2014.
26. Auld AF, Mbofana F, Shiraishi RW, et al.. Incidence and determinants of tuberculosis
among adults initiating antiretroviral therapy—Mozambique, 2004–2008. PLoS One. 2013;8:e54665.
27. Burmen B, Modi S, Cavanaugh JS, et al.. Tuberculosis
screening and management of HIV
-positive patients with TB, Nyanza Province, Kenya, July 2009-August 2010: Proceedings of the 19th International AIDS Conference: Abstract no. MOPE650. July 22-27, 2012, Washington, DC.
28. Storla DG, Yimer S, Bjune GA. A systematic review of delay in the diagnosis and treatment of tuberculosis
. BMC Public Health. 2008;8:15.
29. Monkongdee P, McCarthy KD, Cain KP, et al.. Yield of acid-fast smear and mycobacterial culture for tuberculosis
diagnosis in people with human immunodeficiency virus. Am J Respir Crit Care Med. 2009;180:903–908.
30. Lawn SD, Brooks SV, Kranzer K, et al.. Screening for HIV
and rifampicin resistance before antiretroviral therapy using the xpert MTB/RIF
assay: a Prospective study. PLoS Med. 2011;8:e1001067.
31. Reid MJ, Shah NS. Approaches to tuberculosis
screening and diagnosis in people with HIV
in resource-limited settings. Lancet Infect Dis. 2009;9:173–184.
32. Steingart KR, Sohn H, Schiller I, et al.. Xpert MTB/RIF
assay for pulmonary tuberculosis
and rifampicin resistance in adults. Cochrane Database Syst Rev. 2013;1:CD009593.
33. World Health Organization. Policy Update: WHO Policy Update: Xpert MTB/RIF
Assay for the Diagnosis of Pulmonary and Extrapulmonary TB in Adults and Children. WHO/HTM/TB/2013.16. Geneva, Switzerland: WHO; 2013.
34. Theron G, Zijenah L, Chanda D, et al.. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF
testing for tuberculosis
in primary-care settings in Africa: a multicentre, randomized, controlled trial. Lancet. 2014;383:424–435.
35. Briggs M, Emerson C, Modi S, et al.. Use of isoniazid preventive therapy for tuberculosis
Prophylaxis among people living with HIV
/AIDS: a review of the Literature. J Acquir Immune Defic Syndr. 2015;68(suppl 3):S297–S305.
36. Bock NN, Jensen PA, Miller B, et al.. 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.
37. Rangaka MX, Wilkinson RJ, Glynn JR, et al.. Effect of antiretroviral therapy on the diagnostic accuracy of symptom screening for intensified tuberculosis
case finding in a South African HIV
clinic. Clin Infect Dis. 2012;55:1698–1706.
38. Modi S, Cavanaugh JS, Shiraishi RW, et al.. Symptom-based screening for tuberculosis
among pregnant women living with HIV
in Kenya. 2014; Proceedings of the Conference on Retroviruses and Opportunistic Infections: Abstract no. 812.
39. Hoffmann CJ, Variava E, Rakgokong M, et al.. High prevalence of pulmonary tuberculosis
but Low sensitivity of symptom screening among HIV
-infected pregnant women in South Africa. PLoS One. 2013;8:e62211.