Preventing TB infection in HIV-infected individuals living in medium and high TB endemic settings February 5, 2016 Jeffrey D. Jenks, MD, MPH UCSD HIV & Global Health Rounds

2. Preventing TB infection in HIV-infected
individuals living in medium and high TB-
endemic settings
AIDS Clinical Rounds
February 5, 2016
Jeffrey D. Jenks, MD, MPH
Research Fellow
Division of Infectious Diseases
University of California, San Diego

3. Content
• Epidemiology of TB/HIV
• Risk of TB in HIV
• TB preventive therapy in HIV
• TB risk, immune status, and TB preventive
therapy
• Conclusion

4. Question 1
• Globally, what percent of TB-related deaths
occur in individuals coinfected with HIV?
A. 13%
B. 17%
C. 20%
D. 25%

5. Question 1
• What percent of TB-related deaths globally
occur in individuals coinfected with HIV?
D. 25%

6. Epidemiology of HIV/TB
• “Active” TB cases globally:
- 9.6 million new cases of TB annually
• Of which 1.2 million (13%) in HIV-infected
• 1.5 million TB-related deaths
• Of which 25% in HIV-infected
• Over 1000 TB-related deaths daily in HIV-infected
• TB is among the leading infectious causes of
death globally
WHO, Global TB Report 2015

7. Epidemiology of HIV/TB
WHO, Global TB Report 2015
HIV prevalence in TBI, 2014
TB Incidence, 2014

8. Epidemiology of HIV/TB
• HIV/TB co-infection
• Of 1.2 million with HIV/TB, 74% in WHO
Africa region
• Overall in Africa 39% diagnosed with TB have “known” HIV
– Ranges from 6% in Eritrea to 73% in Swaziland
• HIV/LTBI co-infection
– Estimated that 1 of 3 people globally has latent TB
• Greatest burden in Southeast Asia and Sub-Saharan Africa
– In study of latent TB in gold miners in SA, 30% have
HIV and 89% latent TB
WHO, Global TB Report 2015; Dye C, et al JAMA 1999; Getahun H, et al Clin Infect Dis 2010
Hanifa Y, et al Int J Tuberc Lung Dis 2009

9. TB Pathogenesis
Immunocompetent
Exposure with MTB
bacilli
~70% no evidence
infection - cleared
via innate immunity
30% will have evidence of
infection by TST or IGRA –>
Latent TB
5-10% will develop
active TB within lifetime
~90% continue to
have latent TB
Lin PL and Flynn JL, J Immunol 2010; Marks SM, et al Am J Respir Crit Care Med 2000; Jereb J, et al Int J Tuberc Lung Dis
2003; Zumla A et al, N Engl J Med 2013
~1-2% develop clinical TB –>
Active TB

10. TB Risk
Lawn SD, et al Clin Dev Immunol 2011

11. TB Risk
Lawn SD, et al Clin Dev Immunol 2011

12. Question 2
• In high TB-endemic settings, what percent of
HIV-infected persons present with subclinical
TB?
A. 2.5%
B. 5.0%
C. 10%
D. 15%
Zumla A et al N Engl J Med 2013

13. Question 2
• In high TB-endemic settings, what percent of
HIV-infected persons present with subclinical
TB?
C. 10%
Zumla A et al N Engl J Med 2013

14. Subclinical TB
• Active bacterial replication but no symptoms
• Diagnosed by positive AFB smear/culture or NA
amplification
• High rates of subclinical TB in HIV infection
• Of 93 HIV-infected subjects enrolled in TB booster
vaccine trial in Tanzania:
– 14 (15%) had active TB, including:
• 10/14 (71%) with clinical TB
• 4/14 (29%) with subclinical TB
– Overall prevalence subclinical TB 4.3%
Mtei L, et al Clin Infect Dis 2005

15. Subclinical TB
• Of 213 ART-naïve HIV-infected persons in a single
center in Cape Town, SA
• 18 (8.5%) had “asymptomatic” TB
– 4/18 AFB sputum smear +, 17/18 culture +, 4/14 had
abnormal CXR, 1/18 diagnosed solely by abnormal CXR;
4/18 unreactive TST
• 9/18 developed symptoms between 3 days and 2
months after screening (median 28 days)
– 1 developed disseminated TB within 10 days of enrollment
in study
– Median CD4 count 322 (225-446) in group without TB, 249
(170-322) with subclinical TB, and 148 (64-259) with
symptomatic TB
Oni T, et al Thorax 2011

16. Subclinical TB
• A workplace prevalence survey of 4,668
individuals (19% HIV+) in Zimbabwe
– 27 (0.6%) had TB at prevalence survey screening,
including 13/27 (48%) with HIV
• 12 (44%) of these cases were subclinical TB (4/12 HIV+
and 8/12 HIV-)
• Subclinical TB not only in HIV-infection
Corbett EL, et al PLoS Med 2007

17. Question 3
• An individual with both HIV infection and LTBI
is how much more likely to develop active TB
than someone with LTBI but no HIV?
A. 10 times
B. 20 times
C. 30 times
D. 40 times

18. Question 3
• Over a lifetime, an individual with both HIV
infection and LTBI is how much more likely to
develop active TB than someone without HIV?
C. 30 times

19. HIV and TB risk
• Immunocompetent with LTBI:
– Lifetime risk of developing active TB 5-10%
• 50% developing TB 2-5 years after infection
• Other 50% developing TB subsequent years
• HIV-infected with LTBI:
– At a 5-10% annual risk of developing TB
– Overall 30x more likely to develop TB
– 20-40x increased risk of subclinical TB
Churchyard GJ, et al S Afr Med J 2014; Pawlowski A, et al Plos Pathog 2012; WHO, HIV-associated TB Facts 2013
Macroft A, et al Clin Infect Dis 2013

20. Question 4
• In high TB-endemic settings, what percentage
of HIV-infected individuals who die have
undiagnosed TB infection on autopsy?
A. 15%
B. 22%
C. 30%
D. 40%

21. Question 4
• In high TB-endemic settings, what percentage
of HIV-infected individuals who die have
undiagnosed TB infection on autopsy?
C. 30%

22. Diagnosing TB in HIV
• Diagnosis may be delayed or TB may go undiagnosed:
– Diagnosing LTBI: Anergy to TST and/or IGRA
– Active TB: Poor performance of sputum microscopy in active TB
• Autopsy study of HIV-infected individuals at Hospital in
Johannesburg, SA
– Patients seen from 01/2009-12/2009
– Study of 39 HIV-infected adults
– Median CD4 count 50 cells/mm3
– Diagnosed by needle biopsy and culture
– 14 pre-ART and 25 on ART (15 for <90 days)
– MTB found in 26/39 (67%) of biopsies, immediate cause of death in
15/27 (56%)
– 9/27 (33%) had undiagnosed MTB
Stephan C, et al AIDS 2008; Getahun H, et al Clin Infect Dis 2010; Kramer F, et al Am J Med 1990; Swaminathan S, et al Clin Infect Dis
2010;
Wong EB, et al PLoS One 2012

23. Diagnosing TB in HIV
• Autopsy study of 125 patients at
Hospital in Lusaka, Zambia
– 101/125 (81%) HIV-infected
– Diagnosis by Xpert MTB/RIF of tissue
– 78/125 (62%) had TB, of which 66/78 (85%) had
HIV
– Of those with HIV:
• 20/78 (26%) had undiagnosed TB at death
• 13/78 (17%) MDR TB
Bates M, et al Clin Infect Dis 2015

24. TB Preventive Therapy
• Given increased risk of TB infection in those
with HIV, what can we do to prevent it?

25. TB Preventive Therapy
• Chemoprophylaxis against TB in HIV-infected
individuals in “resource-constrained” settings
• Often termed isoniazid preventive therapy
(IPT) when INH used
• Only used in HIV-infected persons w/o
symptoms or evidence of active TB
• Has been shown efficacious in reducing TB
incidence in medium and high-TB endemic
settings

26. TB Preventive Therapy
• High TB-endemic countries typically include
WHO-designated “high-burden countries”
(HBCs)
– 22 countries with highest incidence of TB
– Account for 80% of all new global TB cases
• TB incidence from these countries range from
Brazil (44/100,000) to South Africa
(934/100,000) population
WHO, Global TB control: A short update 2009
WHO, Global TB Report 2015

27. TB Preventive Therapy
• 22 HBC’s
WHO, Global TB Report 2015

28. TB Preventive Therapy
• In Brazil, 6 months of IPT reduced TB incidence in
TST+, HIV-infected persons
– Cluster randomized study in 29 HIV clinics in Rio de Janeiro
– Of 1954 individuals, 1601 (82%) started 6 months IPT and
353 (18%) did not
– TB rate 0.53/100 PY in IPT group and 6.52/100 PY in no IPT
group
– Effect durable after
median follow-up of 4.8
years (IQR 3.6-6.0)
Golub JE, et al Clin Infect Dis 2015

29. TB Preventive Therapy
• In Haiti, 12 months of IPT effective as well
– RCT in HIV clinic in Port-au-Prince
– Randomized to 12H versus placebo
– Mean follow-up 3 years
– IPT lowers TB incidence
overall and in TST+
Pape JW, et al, Lancet 1993

30. TB Preventive Therapy
• RCT of 2736, HIV-infected adults in Kampala,
Uganda
– Randomized to:
(1) 6H
(2) 3HE
(3) 3HPE
(4) Placebo
Whalen CC, et al N Engl J Med 1997

31. TB Preventive Therapy
Whalen CC, et al N Engl J Med 1997

32. TB Preventive Therapy
• In a meta analysis, 6-12 months of IPT reduced
TB by 30% compared to placebo
• ART alone has been shown to reduce TB
incidence by 70%
• ART + IPT reduced TB by 89% in South Africa
cohort
Akolo C, et al Cochrane Database of Systematic Reviews 2010
Lawn SD, et al Clin Chest Med 2009
Golub JE, et al AIDS 2009

33. Great! So what’s the drawback?
• Protective effect of <12 months of IPT wanes
within 6-18 months in high TB-endemic settings
• Most profoundly demonstrated in Thibela TB
study
– Cluster RCT in 3 gold mines in South Africa
– 40,981 miners in 8 intervention clusters and 37,763
miners in 7 control clusters
• 27,126 (66.2%) miners in intervention clusters screened for
TB and 23,659 (87.2%) given 9 months INH
• 6 months INH dispensed to 35-79% (mean 54.5%) of clusters
• At baseline HIV prevalence 13.6% (self-reported)
Churchyard GJ, et al N Engl J Med 2014

34. Great! So what’s the drawback?
• TBI reduced during treatment (first 9 months):
– Rate 1.10/100 PYs in miners receiving INH versus
2.91/100 PYs in control (RR 0.42)
• After 12 months of follow up:
– Rate 3.02/100 PYs in the intervention clusters
versus 2.95/100 PYs in the control clusters (RR
1.00)
• Protective effect of IPT limited given high rate
of re-infection
Churchyard GJ, et al N Engl J Med 2014

35. Continuous/Extended IPT
Samandari T, et al Lancet 2011
Swaminathan S, et al PLoS One 2012
Martinson NA, et al N Engl J Med 2011
RCTs looking at extended/continuous courses of Isoniazid in HIV-infected individuals in high-TB endemic settings
Study Arms Location Subjects
on ART?
TST/IGRA
status
Efficacy of
extended INH
in preventing
TB
Extended
INH and
mortality
Extended
INH and
serious
adverse
events
BOTUSA trial 6H
versus
36H
Botswana Offered if
CD4 count
<200
TST +, -,
unknown
Decreased
TBI with 36H
No benefit
except in
TST+
subset
No
significant
difference
Swaminathan
S, et al trial
6HE
versus
36H
India Referred
for ART
after
04/2004 if
CD4 count
<250
TST +, - Trend to lower
TBI with 36H
No benefit No
significant
difference
Martinson
NA, et al trial
12HP
versus
12HR
6H
36H
South
Africa
No TST + No lower TBI
in intention-to-
treat analysis
but lower TBI
in post hoc
analysis
Lower in
post hoc
analysis
No
significant
difference
HP = 12 weeks of weekly INH + rifapentine
HR = 12 weeks of twice weekly INH + rifampin

36. WHO Recommendations
• WHO recommends 6 months IPT for all HIV-
infected individuals in “resource-constrained”
settings, regardless of immune or ART status
or if previously treated for TB
– Strong recommendation
• WHO recommends at least 36 months IPT in
high TB incidence settings if TST positive or
TST status unknown
– Conditional recommendation
WHO, Guidelines for intensified TB case-finding 2011
WHO, Guidelines for intensified TB case-finding 2015 update

37. Question 5
• Of the 34 million people living with HIV in
“resource-constrained” settings, how many
were reported to have received IPT in 2014?
A. 1 million
B. 3 million
C. 7 million
D. 10 million

38. Question 5
• Of the 34 million people living with HIV in
“resource-constrained” settings, how many
were reported to have received IPT in 2014?
A. 1 million

39. IPT uptake
• Global IPT provision improved but low
– Of 49 reporting countries, 933,000 HIV-infected
prescribed IPT in 2014
• Increase from 600,000 in 2013
– Coverage ranged from 5% in Swaziland to 97% in
Haiti
• South Africa accounts for 59% of IPT provision
• Still, 77% of countries not reporting data
WHO, Global TB Report 2015

40. TB Preventive Therapy
• Can we increase global provision, prescription,
and uptake of TB preventive therapy, while:
– Maximizing efficacy?
– Maximizing adherence?
– Maximizing cost-effectiveness?
– Minimizing toxicity?
– Increasing patient/provider acceptance?

41. TB as an opportunistic infection in HIV

42. TB Risk and CD4 count
• Observational study of 1480 HIV-infected patients on
ART at HIV Clinic in Cape Town
– Followed for median of
2.1 years
– Evaluated TB incidence by
CD4 cell count strata
– Overall, 203/1480 (13.7%)
developed TB
Lawn SD, et al. AIDS 2009

43. TB Risk and CD4 count
• Observational study of 4590 pre-ART and 3784 on-ART
patients at HIV Center in Anantapur, India
– Looked at TBI and TB-related mortality in in pre- and on-ART groups
– TBI 983/4590 (21.4%) in pre-ART and 540/3784 (14.3%) in on-ART
group
Alvarez-Uria G, et al. J Int AIDS Soc 2014

44. TB Risk and CD4 count
• Observational (sub-study of RCT) of gold miners with
history prior TB in South Africa (pre-ART)
– 338/559 (60%) received daily INH and 221/559 (40%) did
not
– 51 cases of TB, 28/338 (8.3%) in IPT cohort and 23/221
(10.4%) in no IPT cohort
– Rate of TBI varied by CD4 cell count:
Churchyard GJ, et al AIDS 2003
CD4 count category Rate of TBI per 100 PY Significance
<200 18.8/100 p=0.008
200-499 8.6/100
>500 6.9/100

45. TB Risk and CD4 count
• Observational study of HIV-infected cohorts in South
Africa
• Among 2778 individuals after 4287 person-years of
follow-up, 336/2778 given 6H and 2423/2778 no IPT
• TBI rates were:
– No IPT or ART: 7.1/100 PY (CI 6.2-8.2)
– IPT but no ART: 5.2/100 PY (CI 3.4-7.8)
– ART but no IPT: 4.6/100 PY (CI 3.4-6.2)
– ART plus IPT: 1.1/100 PY (CI 0.02-7.6)
• TBI varied by CD4 count
Golub JE, et al AIDS 2009
CD4 count category Rate of TBI per 100 PY Significance
<100 10.7/100 CI 8.4-13.7
100-199 7.0/100 CI 5.5-8.9
200-349 5.2/100 CI 4.1-6.8
>349 4.9/100 CI 3.9-6.0

46. TB Risk and CD4 count
• Trial in India randomized 344 HIV-infected
individuals to 6EH and 336 to 36H
• TBI rate 2.4/100 PY (CI 1.4-3.5) in 6EH and
1.6/100 PY (0.8-3.0) in 36H
Swaminathan S, et al PLOS One 2012

47. TB Risk and CD4 count
• TEMPRANO trial in Cote d’Ivoire randomized participants to:
– “Deferred” (based on WHO guidelines) ART (518)
– “Deferred” ART plus 6 months daily IPT (517)
– “Early” (immediate) ART (520)
– “Early” ART plus 6 months daily IPT (521)
• TB cases:
– Deferred ART, no IPT: 41 cases
– Deferred ART plus IPT: 16 cases
– Early ART, no IPT: 17 cases
– Early ART plus IPT: 11 cases
TEMPRANO ANRS 12136 Study Group, N Engl J Med 2015
Strategy Deferred
ART, no IPT
Deferred
ART +
IPT
Early ART,
no IPT
Early ART +
IPT
Total TB
cases
Baseline CD4 >500/mm3
TB incidence 14 8 8 4 34
Baseline CD4 <500/mm3
TB incidence 27 8 9 7 51

48. Conclusion
• In HIV-infected persons living in medium and high
TB-endemic settings, ART + IPT reduces TBI more
than either ART or IPT alone
• Prolonged course of TB preventive therapy works
the best in high TB-endemic settings
– Extended IPT has been evaluated and may reduce TBI
for those who take it
• Still, TB rate in HIV-infected in medium and high
TB-endemic settings above background rates
after IPT

49. Can we do better?
• Clear correlation between TBI and CD4 cell
count in HIV-infected individuals
• Rationale for targeting therapy duration to
CD4 cell count <500
– Limits duration of therapy to those at highest risk
– Targeting duration may:
• Improve provision and adherence
• Reduce toxicity
• Improve cost-effectiveness

50. Can we do better?
• Most important question:
– Would TB preventive therapy duration, targeted to
those with a CD4 count below a certain threshold
(i.e. <500 cells/mm3), decrease TB incidence to an
acceptable level?
– There is still a risk of TB in those with higher CD4
cell counts
• A well-designed randomized control trial could
best answer this question

51. Questions?

52. References
• Akolo C, Adetifa I, Shepperd S, et al. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database of
Systematic Reviews 2010, Issue 1. Art. No.: CD000171.
• Alvarez-Uria G, Pakam R, Midde M, Naik PK. Incidence and mortality of tuberculosis before and after initiation of
antiretroviral therapy: an HIV cohort study in India. J Int AIDS Soc 2014; 17:19251.
• Bates M, Mudenda V, Shibemba A, Kaluwaji J, Tembo J, et al. Burden of tuberculosis at post mortem in inpatients at a
tertiary referral centre in sub-Saharan Africa: a prospective descriptive autopsy study. Lancet Infect Dis 2015; 15(5):544-551.
• Churchyard GJ, Chaisson RE, Maartens G, Getahun H. Tuberculosis preventive therapy: An underutilized strategy to reduce
individual risk of TB and contribute to TB control. S Afr Med J 2014; 104(5):339-343.
• Churchyard GJ, Fielding K, Charalambous S, Day JH, Corbett EL, et al. Efficacy of secondary isoniazid preventive therapy
among HIV-infected Southern Africans: time to change policy? AIDS 2003; 17:2063-2070.
• Churchyard GJ, Fielding KL, Lewis JJ, Coetzee L, Corbett EL, et al. A trial of mass isoniazid preventive therapy for tuberculosis
control. N Engl J Med. 2014; 370(4):301-310
• Corbett EL, Bandason T, Cheung YB, Munyati S, Godfrey-Faussett P, et al. Epidemiology of tuberculosis in a high HIV
prevalence population provided with enhanced diagnosis of symptomatic disease. PLoS Med 2007;4(1):e22.
• Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated
incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 1999; 282(7):677-
686.
• Getahun H, Gunneberg C, Granich R, Nunn P. HIV Infection-Associated Tuberculosis: the epidemiology and the response. Clin
Infect Dis 2010; 50 Suppl 2: S201-207.
• Golub, JE, Cohn S, Saraceni V, Cavalcante SC, Pacheco AG, et al. Long-term protection from isoniazid preventive therapy for
Tuberculosis in HIV-Infected patients in a medium-burden tuberculosis setting: The TB/HIV in Rio (ThRio) Study. Clin Infect
Dis 2015; 60(4):639-45.
• Golub JE, Pronyk P, Mohapi L, et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South
Africa: a prospective cohort. AIDS. 2009;23(5):631-6.
• Hanifa Y, Grant AD, Lewis J, Corbett EL, Fielding K, et al. Prevalence of latent tuberculosis infection among gold miners in
South Africa. Int J Tuberc Lung Dis 2009; 13(1):39-46.

53. References
• Jereb J, Etkind SC, Joglar OT, Moore M, Taylor Z. Tuberculosis contact investigations: outcomes in selected areas of the
United States, 1999. Int J Tuberc Lung Dis 2003; 7(12):S384-S390.
• Kramer F, Modilevsky T, Waliany AR, Leedom JM, Barnes PF. Delayed diagnosis of tuberculosis in patients with human
immunodeficiency virus. Am J Med 1990; 89(4):451-456.
• Lawn SD, Kranzer K, Wood R. Antiretroviral therapy for control of the HIV-associated tuberculosis epidemic in resource-
limited settings. Clin Chest Med. 2009;30(4):685-99.
• Lawn SD, Myer L, Edwards D, et al. Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during
antiretroviral therapy in South Africa. AIDS. 2009; 23(13):1717-1725.
• Lawn SD, Wood R, Wilkinson RJ. Changing Concepts of “Latent Tuberculosis Infection” in Patients Living with HIV Infection.
Clin Dev Immunol. 2011;2011.
• Ling PL and Flynn JL. Understanding Latent Tuberculosis: A Moving Target. J Immunol. 2010;185(1):15-22.
• Marks SM, Taylor Z, Qualls NL, Shrestha-Kuwahara RJ, Wilce MA, et al. Outcomes of contact investigations of infectious
tuberculosis patients. Am J Respir Crit Care Med. 2000; 162(6):2033-2008.
• Martinson NA, Barnes GL, Moulton LH, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med
2011; 365(1):11-20.
• Mocroft A, Furrer HJ, Miro MJ, Reiss P, Mussini C, et al. The incidence of AIDS-defining illnesses at a current CD4 count > 200
cells/uL in the post-combination antiretroviral therapy era. Clin Infect Dis 2013; 57(7):1038-1047.
• Mtei L, Matee M, Herfort O, Bakari M, Horsburgh RC, et al. High rates of clinical and subclinical tuberculosis among HIV-
infected ambulatory subjects in Tanzania. Clin Infect Dis 2005;40:1500-1507.
• Oni T, Burke R, Tsekela R, Bangani N, Seldon R, et al. High prevalence of subclinical tuberculosis in HIV-1-infected persons
without advanced immunodeficiency: implications for TB screening. Thorax 2011;66(8):669-73.
• Pape JW, Jean SS, Ho JL, Hafner A, Johnson WD Jr. Effect of isoniazid prophylaxis on incidence of active tuberculosis and
progression of HIV infection. Lancet 1993; 342(8866):268-72.
• Pawlowski A, Jansson M, Skold M, Rottenberg ME, Kallenius G. Tuberculosis and HIV co-infection. PLoS Pathog 2012;
8(2):e1002464.

54. References
• Samandari T, Agizew TB, Nyirenda S, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV
infection in Botswana: a randomized, double-blind, placebo-controlled trial. Lancet 2011; 377:1588-98.
• Stephan C, Wolf T, Goetsch U, Bellinger O, Nisius G, et al. Comparing QuantiFERON-tuberculosis gold, T-SPOT tuberculosis and
tuberculin skin test in HIV-infected individuals from low prevalence tuberculosis country. AIDS 2008;22(18):2471-2479.
• Swaminathan S, Menon PA, Gopolan N, et al. Efficacy of a six-month versus a 36-month regimen for prevention of tuberculosis in HIV-
infected persons in India: a randomized clinical trial. PLOS One 2012; 7(12):e47400.
• Swaminathan S, Padmapriyadarsini C, Narendran G. HIV-associated tuberculosis: clinical update. Clin Infect Dis 2010; 50(10):1377-1386.
• TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N
Engl J Med 2015;373(9):808-22.
• Whalen CC, Johnson JL, Okwera A, et al. At trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human
immunodeficiency virus. Uganda-Case Western Reserve University Research Collaboration. N Engl J Med 1997;337(12):801-8.
• Wong EB, Omar T, Setlhako GJ, Osih R, Feldman C, et al. Causes of death on antiretroviral therapy: a post-mortem study from South
Africa. PLoS One 2012; 7(10:e47542.
• World Health Organization. HIV-associated TB facts 2013. Available at:
http://www.who.int/tb/challenges/hiv/tbhiv_factsheet_2013_web.pdf?ua=1
• World Health Organization. Global tuberculosis control: A short update to the 2009 report. WHO/HTM/TB/2009.426. Geneva: WHO,
2009.
• World Health Organization. Global Tuberculosis Report 2015. WHO/HTM/TB/2015.22. Geneva: WHO, 2015.
• World Health Organization. Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with
HIV in resource-constrained settings. 2011. Available at: http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf
• World Health Organization. Recommendation on 36 months isoniazid preventive therapy to adults and adolescents living with HIV in
resource-constrained and high TB- and HIV-prevalence settings. 2015 update. Available at:
http://apps.who.int/iris/bitstream/10665/174052/1/9789241508872_eng.pdf
• Zumla A et al. Tuberculosis. N Engl J Med 2013;368:745-755