MDR-TB in PLHIV: impact and response

Enrico GirardiDepartment of Epidemiology

National Institute for Infectious Diseases “L. Spallanzani”

Rome Italy

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

EMERGENCE OF MDR-TB AMONG PLWHIV AND THE NOSOCOMIAL TRANSMISSION

MDR-TB in PLWHIV: impact and response

HIV/AIDS as a risk factor for MDR-TB in NYC in the 1990’s

Frieden TR et el NEJM 1993

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

HIV-associated multidrug-resistant tuberculosis (MDR-TB) outbreaks in industrialized countries,

1988–1995

Charles D Wells et al. J Infect Dis 2007

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

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

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

“At hospital B, isolates from 30 patientswere tested in 1993 for six additional drugs: all wereresistant 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

Impact of increasing cART uptake on MDR-TB and TB clusters among PLWHIV – Milan , Italy

MDR

Motta D et al , CROI 2010

IS HIV INFECTION A RISK FACTOR FOR TB DRUG RESISTANCE OUTSIDE THE NOSOCOMIAL SETTING?

MDR-TB in PLHIV: impact and response

Pooled prevalence ratio for acquiredMDR-TB and HIV 1.17 (95% CI 0.86, 1.6)

Pooled prevalence ratio for primaryMDR-TB and HIV 2.72 (95% CI 2.03, 3.66)

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)

Pooled prevalence ratio forMDR-TB and HIV Overall1.03 (95% CI 0.78, 1.37)

 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.

Studies from RSA excluded

No association among prevalence of MDR casesand prevalence ofHIV in the studypopulationor in the studycountry

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

PROBLEMS IN MANAGEMENT OF MDR-TB IN PLWHIV: THE CASE OF EUROPE

MDR-TB in PLHIV: impact and response

Impact of Drug-resistance on mortality of TB-HIV patients – NYC 1990’s

Frieden TR et el NEJM 1993

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

Cases Univariate analysis Multivariate analysis

No. MDR-TB %

OR (95% CI) P OR (95% CI) P

HIV statusBelarus2010–2011

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

Ukraine2005-2006

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

Factors associated with TB death among PLWHIV in Europe

Podlekareva et al AIDS 2009

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Presumptive TB

Probable TB

Definite TB without DST

Definite TB with DST

Prop

ortio

n, %

Eastern EuropeN=844

Western EuropeN=152

Southern EuropeN=164

Latin AmericaN=253

Diagnosis of TB and availability of DST results

p < 0.0001

RegionMansfeld M et at - EACS 2013

Anti-TB drug-resistance among patients with DST results within one month of TB diagnosis

Eastern EuropeN=243

Western EuropeN=66

Southern EuropeN=89

Latin AmericaN=61

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Rifampicin and Isoniazid resistant (MDR-TB)p < 0.0001

Rifampicin resistant/Isoniazid susceptiblep = 0.02

Rifampicin susceptible/Isoniazid resistantp = 0.004

Rifampicin and Isoniazid susceptiblep < 0.0001

Prop

ortio

n, %

Eastern EuropeN=243

Western EuropeN=66

Southern EuropeN=89

Latin AmericaN=61

Region Mansfeld M et at - EACS 2013

Susceptibility of empiric anti-TB treatment in relation to subsequent DST results

p < 0.0001Eatern Europe(N=298/830)

Western Europe(N=94/151)

Southern Europe

(N=104/162)

Latin America(N=89/253)

0%

20%

40%

60%

80%

100%

0 active TB drugs

1 active TB drugs

2 active TB drugs

3 active TB drugs

>=4 active TB drugsProp

ortio

n, %

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 EuropeN=298/830

Western EuropeN=94/151

Southern EuropeN=104/162

Latin AmericaN=89/253

Mansfeld M et at - EACS 2013

0

20

40

60

80

100

11 (0-84)

21(6-58)

59 (34-74)

14 (2-68)

30 (10-66)

57 (32-78)

40 (24-58)

MDR-TB,% (95% CI)

0

20

40

60

80

100 96 (80-100)89 (79-93) 88 (82-92) 88 (76-94) 85 (71-93)

74 (58-86)

54 (48-60)RHZ1-based therapy,% (95% CI)

MDR-TB (top) and usage ofRHZ-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

Health care index score

1. WHO defined definite diagnosis of TB2. 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.

Distribution of patients according to HCI score and region of residence

Podlekareva D et al. IJTLD 2013

Kaplan-Meier probability of death in TB-HIV patients stratified according to their HCI score

Podlekareva D et al. IJTLD 2013

• 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.

• 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.

• 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.

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

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