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Assessing the impact of prevalent tuberculosis on mortality among antiretroviral treatment initiators: accurate tuberculosis diagnosis is essential

Lawn, Stephen D.a,b; Gupta, Ankurb; Wood, Robina

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doi: 10.1097/QAD.0b013e3283565ebe
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Westreich et al.[1,2] reported on the association between treatment for pulmonary tuberculosis (TB) at baseline in a South African antiretroviral treatment (ART) programme and subsequent mortality risk. Although patients receiving TB treatment had higher all-cause mortality risk compared with those not treated, no such association was observed after adjustment for baseline CD4 cell count, other patient variables and loss to follow-up (hazard ratio 1.06, 95% confidence interval 0.75–1.49) [2]. This finding was robust when additional death registry data were included and follow-up was extended by 18 months [1].

This finding seems counter-intuitive and we are concerned that some might conclude from these studies that strategies to reduce the burden of TB in ART programmes in sub-Saharan Africa are not important with regard to addressing the high mortality in these programmes. TB is one of the most frequently reported causes of death in this clinical setting [3]. Postmortem studies conducted in Africa (both before and during the ART era) have reported that approximately 30–50% of hospital in-patients who died of HIV/AIDS have evidence of active TB which was often disseminated [4–7]. TB was also identified postmortem in a high proportion of patients in South Africa who died while receiving ART [8]. It must be noted that much disease identified in these studies was undiagnosed at the time of death.

Despite careful statistical analyses and consideration of various potential biases, Westreich and colleagues have not addressed the fundamental issue as to whether patients in their study were accurately classified as having TB or not. This was defined simply on the basis of whether or not they were receiving treatment for pulmonary TB [2]. No case definition for TB disease was used, no microbiological data were presented and extrapulmonary TB was not accounted for. The disease-free comparator group was simply defined as patients not receiving treatment for pulmonary TB at baseline. No systematic microbiological screening of patients was done at baseline to rule out TB, and postmortems were not done to assess for unascertained TB in patients who died in the TB-free group. Moreover, patients developing incident disease during the initial weeks of ART were not excluded from the TB-free comparator group.

Diagnosis of TB in this clinical setting in Africa is challenging due to the nonspecific clinical presentation, high rates of negative sputum smear, extrapulmonary and disseminated disease and comorbidity that may mimic TB [9,10]. As widely used diagnostic tools (sputum smear microscopy and chest radiology) are so blunt and culture is very slow and much less used, there is considerable under-diagnosis as well as some over-diagnosis of TB. Much incident disease diagnosed in the first weeks of ART is actually disease that was present at baseline but missed during screening [11,12]. In studies in which patients enrolling in South African ART clinics with no preexisting TB diagnosis are intensively screened for TB at baseline regardless of symptoms, approximately 15–25% have sputum culture-positive pulmonary TB [13–15].

Potential misclassification of patients into diseased and disease-free groups may substantially undermine the validity of the findings of Westreich and colleagues. We agree with Straetemans et al. [16] that currently available data on TB as a risk factor for mortality in ART programmes are insufficient to draw definite conclusions, as they have considerable limitations. We suspect that TB (especially undiagnosed disease) is a key factor contributing to high early mortality and that strategies to address this should include rapid microbiological screening of all patients regardless of clinical symptoms [9,15,17]. Further well designed studies are therefore needed and accurate disease ascertainment will be essential for these to be interpretable.

Acknowledgements

Conflicts of interest

S.D.L. is funded by the Wellcome Trust, London, UK. R.W. was funded in part by the International Epidemiologic Database to Evaluate AIDS with a grant from the National Institute of Allergy and Infectious Diseases (NIAID, 5U01AI069924-02); Cost-Effectiveness of Preventing AIDS Complications (CEPAC) funded by the National Institutes of Health (NIH, 5 R01AI058736-02); USAID Right to Care (CA 674 A 00 08 0000 700); and the South African Centre for Epidemiological Modeling and Analysis (SACEMA).

The authors have no competing interests to declare.

References

1. Westreich D, Fox MP, Van Rie A, Maskew M. Prevalent tuberculosis and mortality among HAART initiators. AIDS 2012; 26:770–773.
2. Westreich D, MacPhail P, Van Rie A, Malope-Kgokong B, Ive P, Rubel D, et al. Effect of pulmonary tuberculosis on mortality in patients receiving HAART. AIDS 2009; 23:707–715.
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; 22:1897–1908.
4. Lucas SB, Hounnou A, Peacock C, Beaumel A, Djomand G, N’Gbichi JM, et al. The mortality and pathology of HIV infection in a west African city. AIDS 1993; 7:1569–1579.
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; 24:23–29.
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 predominantly HIV-positive patients in Botswana, 1997–1998. Int J Tuberc Lung Dis 2002; 6:55–63.
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 postmortem study. PLoS Med 2010; 7:e1000296.
8. Wong EB, Omar T, Setlhako G, Osih R, Murdoch D, Martinson N, et al.Causes of death in ART-treated adults: a postmortem study from Johannesburg [abstract #WEPE0154]. In: Abstracts of the XVIII International AIDS Conference. International AIDS Society; 2010; Vienna, Austria.
9. 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 (Suppl 4):S1159–S1167.
10. 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.
11. Lawn SD, Myer L, Edwards D, Bekker LG, Wood R. Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa. AIDS 2009; 23:1717–1725.
12. Lawn SD, Kranzer K, Edwards DJ, McNally M, Bekker LG, Wood R. Tuberculosis during the first year of antiretroviral therapy in a South African cohort using an intensive pretreatment screening strategy. AIDS 2010; 24:1323–1328.
13. Bassett IV, Wang B, Chetty S, Giddy J, Losina E, Mazibuko M, et al. Intensive tuberculosis screening for HIV-infected patients starting antiretroviral therapy in Durban, South Africa. Clin Infect Dis 2010; 51:823–829.
14. Lawn SD, Edwards DJ, Kranzer K, Vogt M, Bekker LG, Wood R. Urine lipoarabinomannan assay for tuberculosis screening before antiretroviral therapy diagnostic yield and association with immune reconstitution disease. AIDS 2009; 23:1875–1880.
15. 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; 12:201–209.
16. Straetemans M, Bierrenbach AL, Nagelkerke N, Glaziou P, Van der Werf MJ. The effect of tuberculosis on mortality in HIV positive people: a meta-analysis. PLoS One 2010; 5:e15241.
17. Lawn SD, Brooks SV, Kranzer K, Nicol MP, Whitelaw A, Vogt M, et al. Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: a prospective study. PLoS Med 2011; 8:e1001067.
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