©2013 MFMER | slide-1 Tuberculosis in the Setting of HIV Infection Zelalem Temesgen, M.D....

©2013 MFMER | slide-1

Tuberculosis in the Setting of HIV Infection

Zelalem Temesgen, M.D.Tuberculosis Clinical Intensive

Sept 9-11,2013


Disclosures

• Unrestricted educational grants• Gilead, Janssen, ViiV, Merck, CDC

• Research grants• Gilead, Pfizer, NIH


Learning Objectives

• Describe the epidemiology of TB/HIV co-infection

• Describe the impact of HIV on the natural history of TB

• Describe current guidelines for the diagnosis and treatment of LTBI in the setting of HIV infection

• Explain treatment and management strategies for TB patients with HIV.


Epidemiology


Tuberculosis: 2011 Global Burden of Disease

• 12 million prevalent cases (10-13 million)

• 8.7 million incident cases (8.3-9 million)

• 125 cases per 100 000 population

• Asia (59%) • Africa (26%) • Eastern Mediterranean

Region (7.7%) • Europe (4.3%) • Americas (3%)

• 1.4 million people died from TB in 2011

• 1 million deaths among HIV-negative individuals

• 430 000 among people who were HIV-positive.


Tuberculosis: High-Burden Countries

• Afghanistan

• Bangladesh

• Brazil

• Cambodia

• China

• DR Congo

• Ethiopia

• India

• Indonesia

• Kenya

• Mozambique

• Myanmar

• Nigeria

• Pakistan

• Philippines

• Russian Federation

• South Africa

• Thailand

• Uganda

• UR Tanzania

• Viet Nam

• Zimbabwe


1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

2004

2006

2008

2010

2012

0

5,000

10,000

15,000

20,000

25,000

30,000

No.

of

Cas

es

Year

United States: Reported TB Cases United States, 1982–2012

Data are updated as of 2/22/13 and are provisional

2012 Data9,951 Cases

Rate 3.2/100,000


Reported new tuberculosis cases, by county — United States, 2010–2012

Reported a new TB case

Did not report a new TB case

DC


Rate* of TB Cases by Race/Ethnicity — United States, 2012

2012

Race Rate

Hispanic 5.2

Asian 19.8

Black 5.7

White 0.8

* Per 100,000 populationData are updated as of 2/22/13 and are provisional.

7.3x 6.6x

2012

Race Rate

Hispanic 5.2

Asian 19.8

Black 5.7

White 0.8

2012

Race Rate

Hispanic 5.2

Asian 19.8

Black 5.7

White 0.8

25.0x

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HIV

TB

HIV/TB


TB and HIV Coinfection

• Of the 8.7 million incident cases in 2011, 1.1 million (13%) were among people living with HIV

• In Africa, 39% of TB cases were estimated to be coinfected

• Africa accounted for 79% of TB cases among people living with HIV worldwide


Estimated HIV Coinfection in Persons with HIV Test Results, United States, 1993–2012

% C

oinf

ectio

n

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 20120

5

10

15

20

25

30

Aged 25-44 All Ages


Natural History


HIV Immune Deficiency

• Diminished T cell repertoire

• Reduced lymphocyte function - decreased

• Delayed hypersensitivity response to recall antigens

• Phagocytosis

• Chemotaxis

• Intracellular killing

• Natural killer cell-mediated killing

• Loss of specific antibody responses

• Increased immune activation

• disruption of immunoregulatory cytokine expression and production

• Decreased IL-2, γ interferon, and IL-12

• Increased IL-1, IL-6, TNFα


A Koul et al. Nature 469, 483-490 (2011) doi:10.1038/nature09657

Natural History of M. tuberculosis infection.


Tuberculous infection progressed to active disease within 106 days of acquiring the infection in 37 percent (11 of 30) of HIV-infected patients.

Tuberculosis did not develop in any of 28 staff members with exposures, although there were 6 with documented tuberculin conversions and 8 others had positive tuberculin reactions of unknown duration.


7 of 18 (39%) HIV-infected inpatients developed active tuberculosis within 60 days of diagnosis of the

index case


• Forty-nine HIV-seropositive subjects and 62 HIV-seronegative subjects had a positive TST response.

• Active tuberculosis developed in eight of the HIV-seropositive subjects (4 percent) and none of the seronegative subjects during the study period (P<0.002).


HIV Epidemic State and Estimated Relative Risk of Developing Tuberculosis (TB) in HIVInfected Persons in Comparison with HIV-Uninfected Persons (Incidence Rate Ratio).

Getahun H et al. Clin Infect Dis. 2010;50:S201-S207


Diagnosis of LTBI in HIV-Infected Individuals


Am J Respir Crit Care Med Vol 175. pp 737–742, 2007

• 294 HIV-infected subjects • TST vs. QFT• 89.3% concordance between QFT and TST • only 28% subjects with positive test results by

either TST or QFT had positive test results by both modalities.


• 2348 household contacts of sputum smear positive TB cases followed over 24 months

• Twenty six contacts diagnosed with definite TB• TST sensitivity 56% • ELISPOT 52%• 71% were positive by one or other test• Those negative on either or both tests had the

lowest rate of progression


J Acquir Immune Defic Syndr 2011;56:230–238

• 37 studies with 5736 HIV-infected individuals• Are IGRAs better than TST at predicting which HIV-infected

individuals are at highest risk of progression to active TB? • Are IGRAs more sensitive than TST for diagnosis of MTB

infection in HIV-infected individuals with advanced immunosuppression?

• Insufficient evidence to conclude that either test is superior to the other.


• Testing for LTBI at the time of HIV diagnosis should be routine regardless of epidemiologic risk factors

• Annual testing for LTBI only in those with ongoing exposure• If negative screen for LTBI while CD4 count is low, repeat

testing post cART once CD4 is above 200.• Both TST and FDA-approved IGRAs are appropriate for TB

screening in HIV-infected individuals• Routine use of both TST and IGRAs to screen for LTBI is

not recommended


• 23,517 culture-positive, pulmonary tuberculosis patients from the California tuberculosis case registry from 1993 to 2007 who completed anti-tuberculosis therapy.

• 148 (0.63%) had a late recurrence. • Human immunodeficiency virus infection

(adjusted hazard ratio, 1.81; p = 0.0149


The Journal of Infectious Diseases 2010; 201:704–711

• Retrospective cohort study of South African gold miners, men with known dates of seroconversion to HIV (from 1991 to 1997) and HIV-negative men were followed up to 2004.

• 342 HIV-positive and 321 HIV-negative men who had had1 previous episode of tuberculosis,

• Rates of tuberculosis recurrence:• HIV-positive 19.7 cases per 100 person-years at risk (95% confidence

interval [CI], 16.4–23.7)• 7.7 cases per 100 PYAR (95% CI, 6.1–9.8)


Diagnosis of Active Tuberculosis in the Setting of HIV


TB in the Setting of HIV: Clinical Presentation

• In general, similar to that seen in HIV-uninfected patients

• However, differential diagnosis broader • HIV itself • Other opportunistic infections

• Extrapulmonary• HIV main risk factor• 35-80% vs. 15-50%• Bones and joints, lymph nodes, the pleura,

peritoneum, CNS


Laboratory Diagnosis of Active TB

• Sputum smear• HIV-infected patients are more likely to have smear-

negative pulmonary TB• Range 31 – 81%

• CXR• Individuals with advanced HIV are likely to have

atypical presentations• Lower lobe locations• Less cavities• Consolidation• Intrathoracic LAD• May appear normal


Treatment of Tuberculosis


Treatment of LTBI

Drugs Duration Interval Minimum doses

Isoniazid 9 months Daily 270

Twice weekly* 76

Isoniazid 6 months Daily 180

Twice weekly 52

Isoniazid and Rifapentine

3 months Once weekly 12

Rifampin 4 months Daily 120


Studies of the Effect of Human Immunodeficiency Virus (HIV) Coinfection on the Outcome of Tuberculosis Treatment.

Swaminathan S et al. Clin Infect Dis. 2010;50:1377-1386

© 2010 by the Infectious Diseases Society of America


• Treatment of TB in HIV-infected individuals is the same as for those who are HIV uninfected

• Treatment of TB in HIV-infected individuals should include an initial 4-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol

• DOT is recommended for all patients with suspected HIV-related TB• Daily therapy (5–7 days per week) given as DOT is recommended

during the intensive phase• Daily (5–7 days per week) or thrice-weekly dosing is recommended

during the continuation phase • Once- or twice-weekly dosing during the continuation phase assoc.

with treatment failure/relapse with acquired rifamycin resistance


TB and HIV coinfection: Treatment Issues

• Drug-drug interactions

• Overlapping drug toxicities

• Pill Burden

• Immune-reconstitution inflammatory syndrome (IRIS)

• Sequencing with antiretroviral therapy

• Highly intermittent Dosing

• TB treatment outcome in HIV

• ART treatment effect on TB incidence

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TB/HIV Treatment Issues: Drug Interactions

• Rifamycins induce hepatic cytochrome P450 (CYP3A4) enzymes, accelerating metabolism of:

• Protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), etc.

• Rifampicin >> Rifabutin

• For patients receiving PIs or NNRTIs, substitute rifabutin for rifampin, if available

• Alternative non-rifamycin regimens less optimal, longer duration of therapy

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Rifampicin decreases blood levels of NVP and EFV

NNRTI Effect of Rifampicin

Nevirapine 37–58%

Efavirenz 22%

NNRTIs and Rifampicin


Protease Inhibitor Effect of Rifampicin

Saquinavir by 84%

Ritonavir by 35%

Indinavir by 89%

Nelfinavir by 82%

Amprenavir by 81%

Lopinavir/ritonavir by 75%

Rifampicin decreases blood levels of all PIs

PIs and Rifamycins


Rifamycins and Intermittent Therapy

• Evidence for development of acquired rifamycin resistance with intermittent therapy

• Intermittent therapy not recommended during initial phase of TB treatment in patients with HIV infection

• No twice-weekly continuation phase with advanced immune suppression


Overlapping Side Effects

Side Effect TB Drug ARV

Skin rash* PZA, RIF, INHNevirapineEfavirenzAbacavir

Nausea,vomiting

PZA, RIF, INHZidovudineRitonavirAmprenavir Indinavir

Burman et al, Am J Respir Crit Care Med 2001

* May also see rash with cotrimoxazole


Side Effect TB Drug ARV

Hepatitis PZA, RIF, INH

Nevirapine Protease

inhibitors IRIS

(with chronic hepatitis)

Leukopenia,anemia RIF Zidovudine

Overlapping Side Effects

Burman et al, Am J Respir Crit Care Med 2001


TB/HIV: Barriers to Adherence

• Dual social stigma

• Higher pill burden

• Greater number of potential drug side effects

• Additional illness (opportunistic infections)

• Difficult medical access, drug-supply interruptions


IRIS

Immune Reconstitution Inflammatory Syndrome (IRIS) Clinical worsening in the setting of an

adequate response to ART• “Paradoxical” worsening of previously

known treated (completed or ongoing) opportunistic pathogen

• “Unmasking” of subclinical opportunistic pathogen


Incidence of Tuberculosis Immune Reconstitution Inflammatory Syndrome (IRIS) in Human Immunodeficiency Virus (HIV)–Tuberculosis Coinfection.




IRIS

• Risk factors• Disseminated TB• Shorter delay between onset of TB and ART

drugs• Low baseline CD4, higher baseline viral load• Greater CD4 or viral load response to ART

• Timing of onset• Usually within first 6 weeks of ART (often 2–3

weeks, but can be months after ART started)


IRIS

Clinical presentation:

• Fever

• Nodal enlargement

• Worsening pulmonary infiltrates (with or without respiratory symptoms)

• Local worsening in extrapulmonary sites


IRIS Differential Diagnosis• TB treatment failure

• Drug-resistant TB

• ART failure

• Other opportunistic (or non-opportunistic) infections

• Lymphoma, Kaposi’s sarcoma

• Hypersensitivity drug reactions


IRIS Management• Continue TB treatment

• Continue ART

• Exclude TB treatment failure• Adherence • Drug resistance

• Exclude additional/new diagnosis

• Consider NSAIDS, steroids

• Drainage of lesions


Studies of the Timing of Antiretroviral Therapy (ART) in Human Immunodeficiency Virus (HIV)–Infected Patients with Tuberculosis Undergoing Antituberculosis Therapy.




CD4 Start ART

<50 Within 2 weeks of TB Rx

>50 and TB severe Within 2 - 4 weeks of TB Rx

>50 but TB not severe

Can defer ART beyond 2 - 4 weeks but should start within 8-

12 weeks

HIV-infected TB patients not yet on ART

When to Start Antiretrovirals


Decrease in TB incidence after starting ART in resource-limited, high-burden area

Lawn SD, et al, Am J Respir Crit Care Med, 2008;177:680-685

Antiretroviral Therapy (ART) Significantly Reduces TB Incidence


Tuberculosis/HIV Coinfection: Summary

• Substantial global disease burden, individually and as coinfection

• Bidirectional impact on natural history

• Difficulties in diagnosis and treatment

• TB, even in the setting of HIV, is curable

• ART has tremendous impact on TB incidence in the population

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