MDR-TB in PLHIV: impact and response discusses the emergence and management of multidrug-resistant tuberculosis (MDR-TB) among people living with HIV/AIDS (PLWHIV). Nosocomial transmission of MDR-TB in healthcare settings contributed to outbreaks among severely immunosuppressed PLWHIV in the 1990s. While HIV infection may increase the risk of both primary and acquired MDR-TB, the data on HIV as an independent risk factor for MDR-TB is mixed. MDR-TB has a significant impact on mortality of PLWHIV, with mortality rates in some Eastern European countries found to be unacceptably high. Improving access to drug susceptibility testing, second-line TB

1. MDR-TB in PLHIV: impact and
response
Enrico Girardi
Department of Epidemiology
National Institute for Infectious Diseases
“L. Spallanzani”
Rome Italy

2. Outline of the presentation
• Emergence of MDR-TB among PLWHIV and
the nosocomial transmission
• Is HIV infection a risk factor for TB drug
resistance outside the nosocomial settings?
• Problems in management of MDR-TB in
PLWHIV: the case of Europe

3. EMERGENCE OF MDR-TB AMONG
PLWHIV AND THE NOSOCOMIAL
TRANSMISSION
MDR-TB in PLWHIV: impact and response

5. HIV/AIDS as a risk factor for MDR-TB in
NYC in the 1990’s
Frieden TR et el NEJM 1993

6. Why MDR-TB emerged among persons
living with HIV or AIDS ?
• Pattern of DR resistant in PWLHA may have
been the result of increased circulation of DR
organisms and rapid progression of active
disease of recently acquired infection due to
immunosuppression
• PLWHA may have been more likely to be
exposed to resistant organisms , especially in
the health care setting

8. HIV-associated multidrug-resistant tuberculosis
(MDR-TB) outbreaks in industrialized countries,
1988–1995
Charles D Wells et al. J Infect Dis 2007

9. Factors contributing to the occurrence of
MDR-TB outbreak among PLWHA in the
health care setting
• High concentration in hospital wards of
severely immunosuppressed PLWHIV
• Failure to recognize drug resistance
• Inadequate isolation procedures/facilities
• Inadequate treatment

11. The epidemic is not the result of a point-
source outbreak; rather, a high degree of
interconnectedness allowed multiple
generations of nosocomial transmission

12. In all 19 cases, strains of M bovis
showed resistance to isoniazid, rifampicin,
ethambutol, pyrazinamide, streptomycin,
aminosalicylic acid, clarithromycin, ethionamide,
ofloxacin, capreomycin, and amikacin
XDR-TB nosocomial transmission among
PLWHIV in the 1990’s

13. “At hospital B, isolates from 30 patients
were tested in 1993 for six additional drugs: all were
resistant to amikacin, kanamycin, and terizidon; 24
(80.0%) patients were resistant to cycloserine, 21
(70.0%) to ofloxacin, and two (6.7%) to pyrazinamide”
XDR-TB nosocomial transmission among
PLWHIV in the 1990’s

14. Impact of increasing cART uptake on MDR-TB
and TB clusters among PLWHIV – Milan , Italy
MDR
Motta D et al , CROI 2010

15. IS HIV INFECTION A RISK FACTOR FOR
TB DRUG RESISTANCE OUTSIDE THE
NOSOCOMIAL SETTING?
MDR-TB in PLHIV: impact and response

16. Pooled
prevalence
ratio for
acquired
MDR-TB and
HIV 1.17
(95% CI 0.86,
1.6)
Pooled
prevalence
ratio for
primary
MDR-TB and
HIV 2.72
(95% CI 2.03,
3.66)

17. Pooled prevalence
ratio for MDR-TB
and HIV
Any 1.39 (95% CI
1.14- 1.64)
Primary 2.28
(95% CI 1.54-
3.04)
Acquired 1.24
(95% CI 1.04-
1.43)

18. Pooled
prevalence
ratio for
MDR-TB and
HIV
Overall
1.03 (95% CI
0.78, 1.37)

19. Odds ratio of multidrug resistant tuberculosis (MDR-TB) for HIV positive patients.
A Faustini et al. Thorax 2006;61:158-163
Copyright © BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.

20. Studies from RSA excluded
No association among
prevalence of MDR
cases
and prevalence of
HIV in the study
population
or in the study
country

21. Data from Global Project on Anti-TB Drug Resistance
Surveillance
24 countries 1997–2012
• 11 countries: HIV-positive TB patients had a significantly
higher odds of MDR-TB disease than HIV-negative TB
patients (Estonia Kazakhstan Latvia Republic of Moldova
Russian Federation Ukraine Uzbekistan France Israel
Swaziland Kuwait)
• 1 country: HIV-positive TB patients had a significantly lower
odds of MDR-TB disease than HIV-negative TB patients
(USA)
• 12 countries: No association (Australia Bahamas Belarus
Belgium Benin Cuba Malawi Mexico Namibia Nigeria "
Singapore S Uganda)
• Subgroup analysis: association stronger for primary
MDRTB than acquired MDR-TB
Dean AS, et al.Eur Respir J 2014

22. PROBLEMS IN MANAGEMENT OF MDR-
TB IN PLWHIV: THE CASE OF EUROPE
MDR-TB in PLHIV: impact and response

23. Impact of Drug-resistance on mortality of TB-
HIV patients – NYC 1990’s
Frieden TR et el NEJM 1993

24. Adjusted Cox models:
MDR RH: 2.28 (95%-CI 1.00-5.20)
Disseminated disease: RH: 1.99 (95%-CI 1.10-3.59)
F. Post at al, J Infection 2014
Mortality among HIV+ patients with a TB diagnosis in Eastern Europe –
influence of MDR-TB

25. Cases Univariate analysis Multivariate
analysis
No. MDR-
TB %
OR (95% CI) P OR (95% CI) P
HIV status
Belarus
2010–2011
Negative 1249 44.6 Ref. – Ref.
Positive 72 68.1 2.6 (1.7–4.1) 0.001 2.2 (1.4–3.5) 0.001
Ukraine
2005-2006
Negative 1143 23.8
Positive 307 31.6 1.5 (1.1–2.0) 0.006 1.7 (1.3–2.3) 0.001
I. Dubrovina et al , IJTLD2008 Alena Skrahina IJTLD 2013
HIV infection is associated with MDR prevalence in
the context of high MDR prevalence in Eastern Europe

26. Factors associated with TB death
among PLWHIV in Europe
Podlekareva et al AIDS 2009

27. 0%
20%
40%
60%
80%
100%
Proportion,%
Presumptive TB
Probable TB
Definite TB without DST
Definite TB with DST
Eastern Europe
N=844
Western Europe
N=152
Southern Europe
N=164
Latin America
N=253
Diagnosis of TB and availability of DST results
p < 0.0001
Region
Mansfeld M et at - EACS 2013

28. Anti-TB drug-resistance among patients with
DST results within one month of TB diagnosis
0%
20%
40%
60%
80%
100%
Eastern Europe
N=243
Western
Europe
N=66
Southern
Europe
N=89
Latin America
N=61
Proportion,%
Rifampicin and Isoniazid resistant (MDR-TB)
p < 0.0001
Rifampicin resistant/Isoniazid susceptible
p = 0.02
Rifampicin susceptible/Isoniazid resistant
p = 0.004
Rifampicin and Isoniazid susceptible
p < 0.0001
Eastern Europe
N=243
Western Europe
N=66
Southern Europe
N=89
Latin America
N=61
Region
Mansfeld M et at - EACS 2013

29. Susceptibility of empiric anti-TB treatment
in relation to subsequent DST results
p < 0.0001
0%
20%
40%
60%
80%
100%
Eatern Europe
(N=298/830)
Western Europe
(N=94/151)
Southern Europe
(N=104/162)
Latin America
(N=89/253)
Proportion,%
0 active TB drugs
1 active TB drugs
2 active TB drugs
3 active TB drugs
>=4 active TB drugs
Active drugs calculated from comparing empiric anti-TB therapy and subsequently known DST results
within the first month of TB therapy
p < 0.0001
Eastern Europe
N=298/830
Western Europe
N=94/151
Southern Europe
N=104/162
Latin America
N=89/253
Mansfeld M et at - EACS 2013

30. 11 (0-84)
21(6-58)
59 (34-74)
14 (2-68)
30 (10-66)
57 (32-78)
40 (24-58)
0
20
40
60
80
100
MDR-TB,
% (95% CI)
96 (80-100)
89 (79-93) 88 (82-92) 88 (76-94) 85 (71-93)
74 (58-86)
54 (48-60)
0
20
40
60
80
100
RHZ1-based therapy,
% (95% CI)
MDR-TB (top) and usage of
RHZ-based empiric therapy (bottom) in countries in Eastern Europe
1R=Rifampicin, H=Isoniazid, Z=Pyrazinamide
Country 1 Country 2 Country 3 Country 4 Country 5 Country 6 Country 7
Countries in Eastern Europe
Mansfeld M et at - EACS 2013

31. Health care index score
1. WHO defined definite diagnosis of TB
2. Performance of DST for M. tuberculosis;
3. Inclusion of RIF, INH and PZA) in the initial treatment regimen;
4. Availability of at least one CD4 cell count measurement between 6
months before and 1 month after TB diagnosis;
5. Initiation of cART (a combination of at least three antiretroviral
drugs from any class) before or up to 1 month after TB diagnosis.

32. Distribution of patients according to
HCI score and region of residence
Podlekareva D et al. IJTLD 2013

33. Kaplan-Meier probability of death in TB-HIV
patients stratified according to their HCI score
Podlekareva D et al. IJTLD 2013

34. • Antiretroviral therapy is
recommended for all patients with
HIV and drug resistant-TB requiring
second-line anti-TB drugs,
irrespective of CD4 cell-count, as
early as possible (within the first 8
weeks) following initiation of anti-TB
treatment (strong recommendation
/very low quality evidence)
• The complexity of antiretroviral
regimens and second-line TB
treatment, each with its own toxicity
profiles nd some of which may be
potentiated by concomitant therapy,
demands rigorous clinical monitoring.

35. • Drug-drug interaction studies
of delamanid with tenofovir,
efavirenz and
lopinavir/ritonavir,
respectively, conducted among
healthy individuals who did
not have HIV or TB, suggested
that no dose adjustments
were needed when delamanid
was used with any of these
anti-retroviral agents.
However, there is no published
evidence so far on the use of
delamanid in HIV-infected
MDRTB patients on ART.

36. • bedaquiline be used with
caution in people living with
HIV, …., due to limited or no
information;
• Of note, very limited data are
available on drug–drug
interactions with antiretroviral
medicines, and these are
based on singledose studies
conducted in healthy normal
volunteers. Therefore, people
living with HIV who will be
receiving bedaquiline as part
of MDR-TB treatment should
have their antiretroviral
therapy (ART) regimens
designed in close consultation
with HIV clinicians and ART
specialists.

37. Summary points-1
• HIV infection may favor the emergence and
the spread of MDR TB
• Nosocomial transmission of MDR TB is a
persistent risk for PLWHIV in the context of
high prevalence of severe immunosuppression
• The overall risk of MDR-TB appear to be
increased in for PLWHIV in particular for
primary resistance in comparison to non-HIV
infected persons

38. Summary points- 2
• MDR-TB has a significant impact on mortality of
PLWHIV
• Mortality rates of PLWHIV with MDR-TB are
unacceptably high in some Eastern European
countries
• Aspect of TB care delivery (including low access
to DST and 2nd-3rd line drugs) and low uptake of
cART may contribute to this high mortality
• Scale up of TB and HIV care integration is a
priority