TB in HIV:Management in the “Minefield”

David Ashkin, M.D. Medical Executive Director, A.G. Holley State TB Hospital

State TB Health Officer, Florida Department of HealthAdjunct Assistant Professor, University of Florida College of Medicine

Visiting Assistant Professor, Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine

Co-Principal Investigator, Southeast National TB Center

Disclosure of Financial Relationships

This speaker has no significant financial relationships with commercial entities to disclose.

This slide set has been peer-reviewed to ensure that there areno conflicts of interest represented in the presentation.

Have you ever taken care of a patient with HIV that had or you

thought had TB?1. Yes

2. No

Our Patient• 41 yo African American male presented to a South Florida Hospital

with a two month history of anorexia, 30 lb wt loss, fevers, chills and two week history of increasing shortness of breath and enlarging neck mass. He denied cough or hemoptysis.

• He had a 15 year history of being HIV (+), diagnosed after attempting to donate blood, without a history of opportunistic infections. Has had no antiretroviral therapy in the last 2 years but gives a history of intolerance to NNRTIs but claims to have tolerated indinavir in the past.

• Upon admission, a chest x ray showed a right paratracheal LN enlargement. On physical exam he was found to have a left suppurative anterior cervical mass.

Admission CXR

CT of Neck

Sputum was AFB (+). An aspirate of the cervical mass was AFB (+). The patient was started on 4

anti-tuberculous drugs and was discharged to DOT

TB and HIV at the Turn of the 21st Century

• TB & HIV kills more people worldwide than ever before-2-3 million people die every year-one every 10 seconds• TB & HIV kill more individuals than any other infectious

diseases-Most are 25-44 year old individuals

*Leads to loss of work force*Leads to orphans

-9 million children are orphaned in Africa

Transmission Of Tuberculosis

The CIBA Collection of Medical Illustrations. Volume 7 Respiratory System. Pg 199

Pathogenesis of Tuberculosis

The CIBA Collection of Medical Illustrations. Volume 7 Respiratory System. Pg 200

Disease Progression

• Progression from infection to disease caused by an inability to contain infection

• 5-10% of all HIV(-) will progress from infection to disease

• Up to 8% per year of PPD(+), HIV(+) pts will progress from infection to disease

• The average patient with active TB infects 30 other individuals

HIV and TB:“The Landmines”

• HIV and TB:• TB becomes more common• TB is more difficult to diagnose• TB and HIV are more difficult to manage and treat:

• multiple concomitant infections,• drug-drug interactions,• adverse side-effects,• possible increased rate of relapse,• re-infection,• drug-resistance

• Poorer overall outcomes: ~5-fold increase in mortality

TB Disease Diagnosis “THINK TB!!!”

• Key to diagnosis is awareness of the disease• Think TB Disease whenever you have a patient

that has risks for being infected with TB (eg foreign born, congregate living settings) and/or developing TB (eg HIV, immunosuppression) and present with SUBACUTE (>2 weeks)symptoms:• Current cough• Fever• Night Sweats• Weight Loss

• 30% of HIV (+), active TB cases will have no infiltrates or cavities

TB Disease Diagnosis

• Smear• Cheap & rapid• Only 40-60% positive in cases of active

TB • The Standard for Diagnosis of TB in most

of the world

TB Diagnosis

• Culture• Takes 6-8 weeks by conventional• Takes 1-3 weeks by liquid media• Need ~100 organisms/ml to get 1 colony• Sensitivity-Positive in 80% of CDC Verified Cases• Specificity- 1-2% False Positive

• Susceptibility• Takes 1-2 weeks after positive culture• Molecular Techniques have the ability to give more

rapid results

Most of the world does not have access to these critical laboratory tests!!!

TB DiagnosisNucleic Acid Amplification

• Results within eight hours 99% specificity on smear (+) cases

• Up to 80% sensitivity on three samples

• $30 to $50 per test

• Approved by the FDA for smear-positive and –negative, untreated cases

• May have a rule in non-pulmonary samples

GenoType MTB-DR (Hain Lifescience)

Thanks to a Partnership Grant from the Virginia TB Foundation, the SNTC offers NAA and/or HAIN Testing when Determined to be Necessary

Soon after discharge the patient left to go to Georgia without notifying the health department or taking his TB medications. He returned to Florida 2 months later and represented to the same South Florida

Hospital with a two week history of fever, chills, night sweats, weight loss, productive cough.

CXR 2 months after initial presentation

Cultures from the previous LN aspirate as well as sputum were found to be positive for MTB and

resistant to INH at 2.0ug/ml, and sensitive to the rest of the first line medications. Repeat CXR

revealed the right paratracheal lymphadenopathy. Sputums were again AFB (+). The patient was restarted on 4 drugs and court ordered to A.G.

Holley Hospital (AGH).

Treatment of Active TB Disease

• Start with 4 drugs in all patients• INH, RIF, PZA and EMB or SM until sensitivities return• If pansensitive, D/C EMB or SM• After 2 months of therapy, D/C PZA• Continue INH & RIF for 4 more months for total of 6 months

• Must have culture conversion by 2 months• 6 month regimen good for HIV(-) and (+)• Can use BIW regimen

(TIW ? RIF Monoresistance in HIV pts after daily for first 2 months )• Monitor adherence and toxicity• DOT preferred, Combination pills for self administered

DOT therapy works!

• 95% of patients with TB will be cured by DOT• Decreases morbidity and mortality and cost• Decreases spread of disease

• Average patient with TB infects 30 other individuals• Decreases resistance

• MDR costs ~ $250,000 to cure with only ~ 80% success • 5% of patients with active TB will be unable to complete therapy

requiring legal interventions and facilities to cure them• In S.F. one non-compliant patient with MDR-TB was

responsible for 40 other cases

• AGH Admission labs were significant for an elevated uric acid of 10.2ug/ml, albumin of 3.3, WBC of 10.2k, Hgb of 11.2, Hct of 34, and plt 334k

• VDRL (-), Toxo IgG was (+), IgM was (-)• HIV related labs:

750,000 copies/ml , CD4 count 42 cells/mm3, CD4% 2%, 0.03 ratio• Baseline HIV Genotypic Results: Pansusceptible

• On admission, he was anergic and PPD (-)

Would You Start Antiretroviral Therapy and When?

1. No, Patients with TB should never be started on Antiretroviral Therapy

2. Yes, at the same time as the TB therapy is initiated

3. Yes but wait 2 to 8 weeks after TB therapy is initiated

4. Yes but wait until TB therapy is completed

• The patient was placed on rifabutin (RBT) 300mg/day, EMB 1600mg/day, PZA 1500mg/day and VitB6 50mg/day

• The patient became smear and culture negative after one month of TB therapy, with weight gain and was afebrile.

• Approximately 6 weeks after beginning TB therapy, his RBT (450mg)/PZA/EMB was switched to TIW and the patient was started on Atripla® (efavirenz/tenofovir/emtricitabine) 1 tab po once daily.

• HIV studies at this time was 250,000, CD4<20, 3%, 0.05.

Cohen et. al. Current Opinion in HIV and AIDS 2010, 5:61–69

Should ART be Started and if so When in Patients Receiving TB medications?

Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy

Karim et. al. (CAPRISA group)• Prospective, open-label, randomized, controlled trial in

Durban, South Africa of 642 patients with CD4 counts <500

• 3 groups-a)start ARV (EFV, dDI, 3TC) within 4 weeks of starting TB therapy b)start ARV within 4 weeks of continuation phase of TB therapy c)start ARV within 4 weeks of completing TB therapy

• Due to significant outcomes, group 3 halted after enrollment was complete

• Analyzed groups a and b vs. c

N Engl J Med 2010;362:697-706.

• There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (a and b) (5.4 deaths per 100 person-years, or 25 deaths),as compared with the 213 patients in the sequential-therapy group (group c) (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P = 0.003)

• Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata.

• Rates of adverse events during follow-up were similar in the two study groups.

Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy Karim et. al.

N Engl J Med 2010;362:697-706.

• CROI 2011"These three randomized, controlled trials consistently show

that HIV-infected patients who start TB treatment with <50 CD4 cells/uL should initiate ART during the first weeks. In contrast, for those with >50 CD4 cells/uL, it is less clear that a clinical benefit is associated with starting ART within the first 2 versus 8-12 weeks of TB treatment.“

CROI 2011 Report Selected Topics - Eric S. Daar, M.D. Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine - (03/8/11)

• WHO in their most recent guidelines recommend starting ARV within 2-8 weeks after initiating TB therapy

World Health Organization, “Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach : 2010 Revision,” World Health Organization, Geneva, Switzerland, 2010,

Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy

CDC. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis[online]. 2007. Available from URL: http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm

http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/

HIV & TB Treatment

“CALL AN EXPERT”

Specific Issues • Efavirenz which can be given safely with rifampin (rifabutin not

available in most resource limited areas) without much interference with efficacy and drug levels (esp in populations such as Africa where P450 2B6 516G>T mutation present which increases EFV concentrations)

• Nevirapine preferred in many resource limited areas due to lower cost and availability in combination drug formulations

• Nevirapine levels reduced by rifampin and recent studies suggest efficacy similar to EFV but some conflicting data with large Mozambique CARI-NEMO-ANRS trial results expected 2011.• NVP lead in dosing (200mg daily) not necessary and 200mg BID

can be used from start but data is limited • Boosted PIs should be used with rifabutin

Who should have Therapeutic Drug Monitoring?

• Patients failing treatment• Resistant patients • Patients with possible toxic side effects• Patients with renal or hepatic dysfunction• Drug interactions (eg HIV medications)• Compliance checks

Back to Our Patient

• Approximately twelve days after starting higher dose the patient developed fever, severe neck pain and the sudden onset of quadraplegia.

• Physical exam was significant for no nuchal rigidity but 2-3/5 strength of all four extremities

What is Most Likely Happening at this Time?

1. Toxoplasmosis of the spinal cord

2. Lymphoma of the spinal cord

3. Immune Reactivation with Inflammatory Response (IRIS)

4. Multiple Sclerosis

MRI C-spine

He was started on 100 mg of dexamethasone x 1 and 10 mg q 6h for one wk, and plans

were to progressively taper thedexamethasone over the next 2 mo.

In addition he was started on Pyrimethamine, Sulfadiazine and Cycloserine

MRI C-spine 2 weeks after dexamethasone

He was now able to walk with full strength of all four

extremities. Afebrile, PPD (+).

The pyrimethamine and sulfadiazine were stopped due

to lack of usual response

• Tried tapering steroids over 8 weeks but when got to dexamethasone 2mg BID the lesion and edema increased

• Needle biopsy performed

• Pathology necrotizing granuloma• AFB smear (-), culture negative for TB• PCR (+) TB• When repeat MRI showed an increase in

size an Aminoglycoside and FQ were added but were d/c’d once cultures were negative

• After pathology returned the steroid dose was increased and slowly tapered over 3 months with good results

MRI C-spine 4 months after ARV

• Patient treated for spinal cord TB with one year of TB therapy

• Lesion size remained stable and he remained asymptomatic

• HIV viral load studies remained undetectable

• Patient has done well without relapse and continues HIV therapy

Tuberculosis immune reconstitution inflammatory syndrome “IRIS”

• 2 forms• “Paradoxical TB-IRIS”-Immune reconstitution with inflammatory

response in patients on therapy for TB associated with improved immune function (commonly associated with the initiation of ARV therapy)

• “unmasking TB-IRIS”-patients on ARV therapy who are recognized to have active TB disease within 3 months of initiating ARV therapy • ARV associated TB is the development of TB anytime after

starting ARV therapy

Manabe et al JID 2009:199;437-444

IRIS• Thought to result from rapid recovery of

mycobacterial immune responses resulting in inflammatory reactions to Mycobacterium tuberculosis antigen

• Many published cohort studies of TB-IRIS published with incidence of IRIS reported to be 8-43%

• Risk factors are reported to include: low CD4 cell count, disseminated TB and short interval between starting TB and ART (though some studies show no difference in starting <2 mths vs >2 mths)

TB-IRIS• Most frequently reported features are fever,

enlarging lymph nodes, worsening radiographic features

• Usually beginning 2-12 weeks after starting ART therapy and can last 2 months

• Study from South Africa reporting high prevalence of rifampin resistant disease associated with IRIS*

• Diagnosis of exclusion

*Meintjes et al CID 2009:48:667-678

TB-IRIS• Mortality associated with IRIS is rare except with CNS

involvement• Neurologic involvement has been reported in ~12% of

cases• Most cases treated with supportive care but when life

threatening corticosteroids are used• One randomized placebo controlled study showed

prednisone (1.5 mg/kg/day for 2 weeks followed by 0.75mg/kg/day for 2 weeks) reduced duration of hospitalization and outpatient therapeutic procedures with more rapid symptomatic and radiographic improvement* *Meintjes et al [abstract 34]. In: 16th Conference on Retroviruses and Opportunistic

Infections. Montreal; 2009.

Goals of Public Health for TB• Find and assure the cure of all cases of active TB• Identify those infected with TB who are at the greatest

risk of developing disease• Use “Preventive Therapy” or “Treatment of Latent

Tuberculosis Infection” in those found to be infected to prevent the development of Active Disease and Potentially Prevent Further Spread of the Disease.

• These interventions reduce morbidity and mortality to the patient as well as reduce spread to the community

• Very resource dependent, especially when completion of LTBI Therapy is expected (Health Departments WILL have decreasing resources that may affect effective completion of CI activities)

Latent TB Infection & HIV• Recommended that all patients with active TB or LTBI be tested

for HIV• All persons should be tested for LTBI at the time of HIV diagnosis

regardless of their TB risk category (AII). • Persons with negative diagnostic tests for LTBI, advanced HIV

infection (CD4+ count <200 cells/μL), and without indications for initiating empiric LTBI treatment should be re-tested for LTBI once they start ART and attain a CD4+ count >200 cells/μL (AIII).

• In general, annual testing for LTBI is recommended for HIV-infected persons who are or remain in a “high-risk” category for repeated or ongoing exposure to persons with active TB, i.e., persons who are or who have been incarcerated, live in congregate settings, are active drug users, or have other sociodemographic risk factors for TB (AIII).

Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. MMWR 2009; 58:RR-4

Diagnosis of TB Infection:Tuberculin Test

The CIBA Collection of Medical Illustrations. Volume 7 Respiratory System. Pg 205

Sensitivity and Specificity of the Tuberculin Skin Test (TST)

• Depending on prevalence of disease in population you are testing and geographical area• Up to 20% of positive reactions might be false positives

• Infected with Mycobacteria other than TB (e.g. MAC)• BCG vaccine

• Up to 20% of individuals with active TB may be false negative• Critically ill TB patient• Immunosuppressed person• Recently vaccinated with live virus• Recent TB infection

Alternatives to PPD: Specific Mycobacterial Antigens

NTM

BCGM.

tuberculosis

Target area

Interferon Gamma Release Assays (IGRAs) for LTBI

• IGRAs recently approved by FDA (Quantiferon© Cellestis, T-Spot© Oxford Immunotec)

• Guidelines from the CDC now recommend that the use of such interferon-γ release assays for MTB (IGRA) may be used in all circumstances in which the TST is currently used, including contact investigations, the evaluation of recent immigrants, and sequential testing surveillance programs for infection control (eg, those for healthcare workers)

• May be able to discern reaction to BCG and NTM• More studies needed to discern role in LTBI diagnosis (especially

performance in certain populations eg, young children and immunosuppressed persons)

Comparison of IGRAs and TSTIGRA:

• In vitro test• Specific antigens• No boosting• 1 patient visit• Minimal inter-reader

variability• Results in 1 day• Requires blood test• May needs to get to Lab

within 16 hrs

TST• In vivo test• Single antigen• Boosting Phenomenon• 2 patient visits• Inter-reader variability• Results in 2-3 days• No phlebotomy• Done on site

Problem with Diagnosing LTBI

• No Gold Standard• “Do we really have to care?”

Predictive Value of QFT

• For QFT, 198/954 (20.8%) were positive; 63.3% (604) were TST positive at > 5mm and 25.4% at > 10mm

• 903 contacts refused chemoprevention and 19 developed active TB.• All 19 (100%) had been QFT-positive with a progression rate of 12.9%

(19/147) over the observation period• The corresponding rates for progression to active TB during the follow-up

period were 12.9% (19/147) for QFT-positive contacts, significantly higher than the 3.1% rate (17/552) of those positive by the TST using a >5mm cutoff (p < 0.0001)

• IS6110 genotyping of M. tuberculosis isolates revealed that for all eleven culture positive patients the infective strain matched that of the respective index case

• QFT had maximal negative predictive value with none of the 413 TST positive QFT-negative subjects progressing to active TB disease

Diel et al Am J Respir Crit Care Med Vol 183. pp 88–95, 2011

IGRAs for LTBI in HIV: Meta-Analysis• 37 studies involving 5736 HIV infected individuals• The risk of active TB was higher in HIV infected individuals with a

positive IGRA result vs. Negative IGRA result• Pooled sensitivity estimates were heterogenous but higher for Tspot

TSPOT (72%; 95% confidence interval, 62–81%) than for QFT-GIT (61%; 95% CI, 47–75%) in low-/middle-income countries

• However, neither IGRA was consistently more sensitive than the tuberculin skin test in head-to-head comparisons

• Although TSPOT appeared to be less affected by immunosuppression than QFT-GIT and the tuberculin skin test, overall, differences among the three tests were small or inconclusive

• “Conclusions: Current evidence suggests that IGRAs perform similarly to the tuberculin skin test at identifying HIV-infected individuals with latent tuberculosis infection. Given that both tests have modest predictive value and suboptimal sensitivity, the decision to use either test should be based on country guidelines and resource and logistic considerations.”

Cattamanchi et. al. J Acquir Immune Defic Syndr 2011;56:230-238.

• An IGRA or a TST may be used without preference to test recent contacts of persons know or suspected to have active tuberculosis with special considerations for follow-up testing.• An IGRA may be preferred for testing persons from groups that historically

have low rates of returning to have TSTs read.• IGRAs offer the possibility of detecting M. tuberculosis infection with greater

specificity than with a TST. • Also, unlike TSTs, IGRAs do not boost subsequent test results and can be

completed following a single patient visit.• However, data on the ability of IGRAs to predict subsequent active tuberculosis

are limited.• If IGRAs are to be used in contact investigations, negative results obtained prior

to 8 weeks after the end of exposure typically should be confirmed by repeat testing 8–10 weeks after the end of exposure. This recommendation is similar to one used for TST, because data on the timing of IGRA conversion after a new infection are not currently available.

CDC IGRA Guidelines 2010

CDC. Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection-United States, 2010. MMWR. 59:RR-5.

Treatment of LTBI

1. INH x 9 mo daily or BIW (DOPT): 75% effective

2. INH x 6 mo daily or BIW (DOPT): 65% effective

3. Rifampin x 4 mo daily: Limited data on effectiveness. Higher compliance/completion• Well Tolerated, Cost Effective• BUT: use with caution in HIV as TB can be difficult to diagnosis

and could develop rifampin resistance

4. RIF/PZA daily x 2 mo or BIW (DOPT) : Not recommended due to risk of hepatotoxity

5. ? INH/rifapentine once weekly for 12 weeks

CLINICAL AND MONTHLY LFT MONITORING RECOMMENDED IN HIV PATIENTS

MUST FIRST RULE OUT ACTIVE TB!!!!!!!

Southeast National TB Center/

A.G. Holley TB Hotline1-800-4TB-INFO

Disclosure of Financial Relationships

This speaker has no significant financial relationships with commercial entities to disclose.

This slide set has been peer-reviewed to ensure that there areno conflicts of interest represented in the presentation.