overview

Overview• Background

• HIV and tuberculosis syndemic • Pathophysiology, clinical manifestations• Epidemiology

• Diagnosis• Management

• What drugs to use• When to start ART• IRIS and drug interactions

• Prevention of TB & HIV Advances• IPT• ART• Infection Control

• Unmet Needs & Recommendations

What is a Syndemic? “A set of linked health problems involving two or more afflictions, interacting synergistically, contributing to excess burden of disease in a population.”

Linked epidemics, interacting epidemics, connected epidemics, co-occurring epidemics, co-morbidities, and clusters of health-related crises

http://www.medterms.com/script/main/art.asp?articlekey=22591

http://www.medterms.com/script/main/art.asp?articlekey=22591

TB Pathophysiology & Clinical Manifestations

TB PathophysiologyEtiology: Mycobacterium tuberculosis complex

Small PM, Fujiwara PI. N Engl J Med 2001;345:189-200

Airborne droplets (1-5 μ)

~36-50% lifetime risk

~10% lifetime

risk

Clinical Sites of TBTB Cases by Site, 2012*• Pulmonary (PTB) 68.5• Both PTB and EPTB 10.2• Extrapulmorary (EPTB) 21.1

• Miliary 3.5

* CDC. Reported Tuberculosis in the United States, 2012. Atlanta, GA. Dept HHS Oct 2013

78.7%

Goals of Anti-TB Chemotherapy• Individual benefits

– Prevent morbidity and mortality• Kill bacilli rapidly (rifamycins play key role)• Prevent drug resistance (multidrug therapy)• Eliminate persistent bacilli relapse

• Public health benefits – Prevent transmission (identify contacts

in need of treatment for LTBI or active TB)

– Protect effective drug regimens

Epidemiology (TB and HIV-associated associated TB) in U.S. and Globe

Reported TB Cases United States, 1982–2013*

1985-1992 Resurgence• HIV• MDR TB• Immigration• Institutional transmission• Weak infrastructure

2013 Data9,588 Cases

Rate 3.0/100,000

* MMWR 2013;63:229-33

HIV-Associated MDR TB Outbreaks,

1988-1995 and 2006Evidence of institutional MDR TB transmission

Wells CD, et al. J Infect Dis 2007;196:S86-S107; Gandhi NR et al. Lancet 2006;368:1575-80

Hospital KZN, South Africa, 2006 53 100 98 2

Reporting of HIV Test Results in Persons with TB by Age Group,

United States, 1993 – 2012*

*Updated as of June 10, 2013.Note: Includes persons with positive, negative, or indeterminate HIV test results and

persons from California with co-diagnosis of TB and AIDS. Rhode Island did not report HIV test results for years 1993–1997. HIV test results for Vermont are not included for years 2007–2010. HIV test results for California are not included for years 2005 - 2010

% w

ith T

est R

esul

ts

Estimated HIV Coinfection in Persons

Reported with TB, U.S., 1993 – 2012*

Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group

% C

oinf

ectio

n

CDC. Reported Tuberculosis in the United States, 2012. Atlanta, GA. Dept HHS Oct 2013

TB Case Rates by Race/Ethnicity,* United States, 2003–2012**

*All races are non-Hispanic. **Updated as of June 10, 2013.

Cas

es p

er 1

00,0

00

TB Case Rates in U.S.-born vs. Foreign-born Persons, United

States,* 1993 – 2012**

* TB case-rates presented on a logarithmic scale.**Updated as of June 10, 2013.

Cas

es p

er 1

00,0

00

HIV Prevalence and IncidenceUnited States, 1980-2010

Number of people living with HIV has grown because incidence is relatively stable and survival has increased

Hall HI et al. JAMA 2008 Aug 6;300(5):520-9; Prejean J et al PLoS One 2011;6(8):e17502; MMWR 2012 Mar 2;61(8):133-8.

Estimated Number of Adults and Adolescents Living with HIV Infection and Percent Undiagnosed, U.S., 1985-

2008

Estimated HIV prevalence among new TB cases, 2012

Total: 35.3 million [32.2 million – 38.8 million]

Western & Central Europe

860 000[800 000 – 930

000]

Middle East & North Africa260 000

[200 000 – 380 000]

Sub-Saharan Africa25.0 million

[23.5 million – 26.6 million]

Eastern Europe & Central Asia

1.3 million [1.0 million – 1.7 million]

South & South-East Asia3.9 million


Oceania51 000

[43 000 – 59 000]

North America1.3 million

[980 000 – 1.9 million]

Latin America1.5 million


East Asia880 000

[650 000 – 1.2 million]

Caribbean250 000

[220 000 – 280 000]

Adults and children estimated to be living with HIV, 2012

Estimated HIV-associated TB incidence and mortality globally,

1990-2012

In 2012: 8.6 million TB cases (1.3 million deaths ) 1.3 million (13%) with HIV – 75% in AFRO 450,000 with MDR TB (170,000 deaths)

Diagnosis & Management/ Rx Needs

Clinical Signs & Symptoms - Pulmonary TB

Pulmonary Symptoms:

• Productive, prolonged cough of over 3 weeks duration

• Chest pain• Hemoptysis

Systemic Symptoms:

• Fever• Chills• Night sweats• Appetite loss• Weight loss• Easy fatigability

Armitige LY. U Texas HSC Tyler

Challenges of Diagnosing HIV-related TB

• Frequency and broad spectrum of lung disease among patients with HIV/AIDS

• Rapid progression of HIV-related TB and possibility of transmission to others – need for quick diagnosis

• Effects of immunodeficiency on clinical symptoms and signs of TB

Burman WJ. 2008

Challenges in HIV-associated TB Diagnosis

• Paucibacillary• Atypical CXR• Extrapulmonary*

Treatment• Drug-drug

interactions between rifamycins and ARV

• Inmune reconstitution inflammatory syndrome

Pulmonary TB

Early HIV

(CD4>350)

Advanced HIV

(CD4<200)

Clinical Post-primary

Primary TB

Sputum AFB

Positive Negative

Chest Radiograph

Cavitary Infiltrates

With extra-pulmonary TB

Occasional Common

* Lymphatic, meningeal, milliary, disseminated (mycobacteremia)

Effect of HIV-induced Immunosuppression on CXR

Presentation of TB • CD4 > 200– Upper lobe, fibronodular– Cavitation

• CD4 < 200– Upper or lower lung field involvement– Absence of scarring and cavitation– Miliary or nodular infiltrates– Intrathoracic adenopathy, with necrosis– Pleural and pericardial involvement

Extrapulmonary manifestations of TB, by CD4+ T-lymphocyte count range

0

10

20

30

40

50

60

70

80

>300 201-300 101-200 0-100

% w

ith

ext

rap

ulm

on

ary

invo

lvem

ent

Jones BE et al. Am Rev Respir Dis 1993;148:1292-7

Common Forms of Extrapulmonary TB in HIV-infected Persons (Burman

WJ. 2008)

• Nodal – peripheral nodes: cervical > axillary > inguinal– central nodes: mediastinal > hilar, intra-

abdominal

• Disseminated disease• Serosal - pleural, pericardial > ascites• Central nervous system - meningitis,

tuberculoma• Soft tissue abscesses

http://generalsurgeryclinics.blogspot.com/2013/02/clinical-pleomorphism-tuberculosis.html

• Influenced mostly by degree of immunity

• HIV-positive patients are more likely to have:– Isolated extrapulmonary localization (53-63% in some studies)

– Primary infection– Pulmonary basilar involvement– Tuberculous pneumonia– Hilar or mediastinal lymphadenopathies– Miliary or disseminated TB– Normal CXR (8-20% in some studies)

Clinical PresentationHIV-positive vs HIV-negative

patients

Aaron L et al. Clinical Microbiology and Infection 2004;10 (5): 388-98

When Should You Start ART in a Patient with Active TB?

Options:

1. At time of TB treatment initiation2. 2-8 weeks after TB medications are

started3. After TB treatment is completed4. Not at all

N Engl J Med 2010;365:1471-81

N Engl J Med 2011;362:697-706

Early Timing of ART Therapy in TB-HIV

PRO:– High mortality without ART– Beneficial effect of HAART on other OIs– ART decreases risk of TB relapse

CON:– Large pill burden for TB and HIV

regimens– Drug-drug interactions and toxicity– IRIS risk increased

Ruling Out TB in HIV-infectedBefore Isoniazid Preventive

Therapy

Cain KP, et al. N Eng J Med 2010;362:707-16

Symptoms % Sensitivity

Cough <3wks 33

Cough or fever or 3wkNS 93

• NPV 97%

151 (61%) of 249 TB cases had two negative AFB smears

12–dose Isoniazid and Rifapentine Regimen for LTBI in PLWH

Sterling T, et al. CROI 2014. Abstract 817

Starting ART During TB Treatment – Steps Required

1. Start TB therapy: deal with initial side effects

2. Help patient deal with 2 new diagnoses

3. Begin PCP prophylaxis if CD4 < 200

4. Coordinate start of ART: usually 2 weeks after TB treatment start

5. Use DOT visits to adherence with ART

6. Anticipate and manage IRIS events

ART and TB Therapy

Approach to building a regimen: 1. Use a rifamycin2. Use efavirenz and rifampin as

preferred regimen3. Alternative: Use rifabutin with PI

EFV-based ART with RIF-based TB therapy

• Modest reduction in EFV levels does not appear to reduce EFV activity

• EFV-based ART (600 mg) with RIF-based TB therapy is regimen of choice

Rifabutin and TB Therapy

• Rifabutin is as active as rifampin• No dose adjustments of ART needed

for commonly-used drugs (ATZ, lopinavir/R)

• Decrease RBT from 300 mg daily to 150 mg thrice-weekly for boosted PIs

*Caution – RBT dose would be inadequate if patient stopped PI

Summary – Treatment of HIV TB

• How long should TB treatment be given?

– 6-9 months*

• Can intermittent therapy be used in someone with advanced HIV disease?

– Daily preferred

– After the intensive phase, can use thrice-weekly

– Avoid highly-intermittent Rx if CD4 low

* Extend treatment to 9 months if culture-positive at 2 months or extensive bilateral cavitary pulmonary disease

Summary-Treatment of HIV TB• Should antiretroviral therapy be used during TB

treatment?– Yes

• What regimens can be used for co-treatment of HIV and TB?– Preferred: efavirenz-based ART + rifampin-

based TB treatment– Alternative: PI-based ART + rifabutin-based

TB treatment• When should HAART be started?

– 2 weeks to 2 months after starting TB treatment

Side Effects & Drug-to Drug Interaction

Overlapping Side Effect Profiles of First-lineTB drugs and Antiretroviral (ART) Drugs

Side effect

Possible causes

TB drugs ART drugs

Skin rash

Nausea, vomiting

Hepatitis

Leukopenia, Anemia, platelet decrease

PZA, RIF, INH

PZA, RIF, RBT, INH

PZA, RIF, RBT, INH

RBT, RIF

NVP, EFV, ABC

AZT, PIs

NVP, PIs, IRIS

AZT

Immune Reconstitution Inflammatory Syndrome (IRIS)

Paradoxical Worsening of TB following ARTHow Common?

Immune Reconstitution Inflammatory Syndrome (IRIS)

Possible Risk Factors

Manosuthi W et al. Journal of Infection 2006;53:357-363

Diagnosing IRIS

Meintjes et al. Lancet Infect Dis 2008;8:516-23.

IRIS

Management

• Exclude treatment failure or new OI• Continue anti-TB and ART• NSAIDS• For severe symptoms: steroids (40 to 80

mg/d) for 5 to 14 weeks

Furrer, Am J Med, 1999.

Mansouthi W

Prevention and Treatment Advances

1995-2012 Global TB Response Initially DOTS, Later Global Plan

56 million people successfully treated for TB

22 million lives saved Improvements in TB/HIV

prevention and care 46% of TB patients tested for HIV in

2012, 74% in Africa 57% TB patients known to be living

with HIV enrolled on ARVs, 80% received CPT

Diagnosis and treatment of MDR-TB doubled between 2011 and 2012 , with case rates falling in some countriesWHO/HTM/TB/2013.11

Collaborative TB/HIV activities, 201253 |

The 2012 WHO PolicyThe 2012 WHO Policy


Number of TB patients with known HIV status 2004-2012

Number of TB patients with known HIV status 2004-2012


Number of HIV-positive TB patients enrolled on co-trimoxazole preventive therapy (CPT) and

antiretroviral therapy (ART), 2004-2012

Number of HIV-positive TB patients enrolled on co-trimoxazole preventive therapy (CPT) and

antiretroviral therapy (ART), 2004-2012


Provision of isoniazid preventive therapy (IPT) to people living with HIV without active TB, 2005-2012Provision of isoniazid preventive therapy (IPT) to

people living with HIV without active TB, 2005-2012


Collaborative TB/HIV activities 2004-2012Global

Collaborative TB/HIV activities 2004-2012Global


Estimated number of lives saved globally by the implementation of TB/HIV interventions, 2005-2011Estimated number of lives saved globally by the

implementation of TB/HIV interventions, 2005-2011

Blue band represents the uncertainty interval

Evolution of Global TB Strategy

Post–2015 Global TB TargetsFar more needs to

be done!• Est. 3 million with TB

disease “missed” (nearly 1/3)

• 1.3 million died of TB in 2012 (320,000 with HIV)

• Almost ¾ of MDR TB not diagnosed or treated properly

• More than half of TB patients unaware of HIV status

• 530,000 children ill with TB in 2012

WHO/HTM/TB/2013.13

Frieden TR. AJPH 2010;100:590-595

Convergence of Thought in HIV Continuum of Care Initiative and

Post –2015 TB StrategyElement HIV Continuum of Care Post-2015 TB Strategy

Political Will POTUS Executive Order WHA 2012 call to action

Support Integration of Prevention and Care

Yes Yes (with attention to infection control and LTBI)

Promote Expansion of Service Delivery Models

Yes Yes

Encourage Innovative Approaches

Yes Yes (new way of thinking beyond DOTS strategy)

Attention to Health Disparities

Yes Yes (bold policies for universal coverage)

Research for Evidence-based Interventions

Yes Yes

Measurable Targets with Monitoring of Outcomes

Yes Yes

Treatment As Prevention Yes Yes

Ambitious Yes Yes (DOTS initially not)

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Surveillance

Capacity Building Assistance for MSM & High Risk Populations

ART Adherence interventions

Support and Guidance for Health Departments & CBOs

Lab Reporting and Surveillance

Prevention with Positives Guidelines and Research

Health Department Prevention FOA

Partner services

Testing guidelines

Social marketing campaigns

MSM Testing Initiative New FOA

with HRSA for CHCs

Health Services Research

CAPUS

ARTAS

ART guidelines

Health Department and CBO support

Filling in the Gaps Along the HIV Care Continuum

Unmet Needs & Recommendations

Unmet Needs

New, less toxic anti-TB drugs for PLWH on ART

Shorter treatment regimens

Treatment for presumed LTBI due to MDR

Safe and effective TB vaccine(s)

Recommendations Manage both HIV and TB Test all TB patients for HIV and link to care

• Start treatment on ARVs and treat for TB• Be on alert for DDI and IRIS

Implement and monitor infection control in HIV clinics

Screen PLWH for TB and treat LTBI Utilize ARVs to reduce risk of TB Advance Treatment as Prevention (TASP) Promote and monitor adherence to

treatment Monitor outcomes

THANK YOU

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

Division of HIV/AIDS Prevention

Publications and Resources

Available by visiting CDC’s DHAP and DTBE websites:

http://www.cdc.gov/hiv/

http://www.cdc.gov/tb/

Or by calling:1-800-CDC-INFO

http://www.cdc.gov/hiv/



overview

Documents

associated tb

tb preventioncenters

mdr tb outbreaks

indeterminate hiv test

reporting of hiv test

codiagnosis of tb

linked epidemics

cooccurring epidemics