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TB-HIV Update Asilomar 2006. Jacqueline Tulsky, MD SF AETC and SFGH Positive Health Program L. Masae Kawamura M.D Director, San Francisco TB Control Francis J. Curry National TB Center. TB “ Must Knows”. MDR-TB and its Scary Offspring The International Standards for Tuberculosis Care

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TB-HIV Update

Asilomar 2006

Jacqueline Tulsky, MD

SF AETC and SFGH Positive Health Program

L. Masae Kawamura M.D

Director, San Francisco TB Control

Francis J. Curry National TB Center


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TB “ Must Knows”

  • MDR-TB and its Scary Offspring

  • The International Standards for Tuberculosis Care

  • CDCP Contact Investigation Update

  • Use of Quantiferon-Gold

  • A Word on TB-ARV Interactions


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But First…

A patient with active TB…

1. I have diagnosed or treated

2. I have helped take care of

3. I have never seen


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Why TB and HIV?

Major opportunistic infection in HIV that is spread through an airborne route

Able to cause disease in immunocompetent contacts

“Until TB is a problem no where, it will be a problem everywhere” Lee Reichman


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Global Importance of TB and HIV

TB is (still) the leading cause of death among AIDS patients worldwide

Among the biggest treatment dilemmas is how to manage TB/HIV at the same time



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A Picture of…

1. Positive TB skin test

2. Last night’s sausage pizza

3. Acid Fast bacillus on a slide


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AFB on a Slide

Tubercle bacilli w/ Ziehl-Neilsen stain. Most larger US labs use

Oramine-Rhodomine w/ darkfield microscopy


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No Fear?

Fear This!

XMDR TB


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XDR-TB: 8/23/06

“Rapidly Fatal in South Africa” Tugela Ferry, KwaZulu-Natal

  • 10% isolates resistant to ALL 1st and 2nd line agents

  • 51/52 XDR dead in median 16 days after first positive sputum

  • 67% AIDS deaths w/ MDR TB


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MDR-TB definition

  • MDR-TB: Resistance to both INH and rifampin

  • XDR-TB: Resistance to INH and rifampin and at least 3 of the 6 main classes of 2nd line agents (New classification)


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MDR-TB: Global RatesZignol, Dye et al, JID 2006:194

2002 : 272,906 (1.1%)

2004 : 424,203 (4.3%)

  • Estimated 43% of global MDR-TB cases have had prior treatment

  • China, India and Russian Federation accounts for 62% of the MDR burden


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2006 Global Distribution of MDR-TB among previously treated cases Source: Zignol, Dye et al, JID 2006:194


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Impact of drug resistance on TB cure rates with standard 4-drug therapy

Espinal, JAMA 2000; 283:2537


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XDR-TB: 9/8/2006 4-drug therapy

“Found in 28 hospitals in

South Africa”

  • Initial cases identified “several” years ago

  • HIV can fast track XDR-TB to uncontrollable epidemic

  • KwaZulu-Natal deaths associated with 1 healthcare worker and ARVs


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XDR-TB: 9/20/2006 4-drug therapy

“Clusters..in Iran involve pts w/ HIV”CID 10/1/06

  • 1,284 Active TB Cases 2003-05

  • 1% of all TB cases, 11% of all MDR-TB were XDR-TB

  • No cases were previously treated TB


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International Standards of Tuberculosis Control (ISTC) 4-drug therapyThe Guidebook to International TB


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ISTC Standard 14 - Drug Resistance 4-drug therapy

Assess ALL patients for drug resistance

  • History of prior treatment

  • Exposure to possible drug resistant source case

  • Community prevalence of drug resistance


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ISTC Standard 15 - Drug Resistance 4-drug therapy

Individualized MDR-TB treatment

  • Special regimens with at least 4 susceptible drugs

  • Minimum treatment is 18 months

  • “Patient-centered measures are required to ensure adherence”

  • Consult an expert or provider experienced in treating MDR-TB


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Emergency Action Plan from CDC, WHO, SA Research Council 4-drug therapy

  • Rapid survey to detect XDR-TB

  • Enhance lab capacity for detection

  • Improve TA to respond to XDR outbreaks

  • Implement infection control precautions, especially w/ HIV pts

  • Increase research support for TB drugs and rapid diagnostic tests


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CDCP Contact Investigation Update 4-drug therapyMMWR Vol 54/RR-15 12/2005

  • Prioritizing contacts based on risk of developing TB

  • Specific contact investigation time-to-completion goals

  • Investigation of social networks and congregate settings

  • Window Period LTBI Rx


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Finding LTBI 4-drug therapy

  • 38 yr old man, HIV infected health care worker just back from 2 months in Uganda. He is worried about TB infection. His last TB test was negative, but his CD4 ct is 280 cells/mm3

  • What is the most reliable way to be sure he has not been infected with TB while in Africa?


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1. PPD TB skin test for LTBI 4-drug therapy

2. Blood test to screen for LTBI

3. Paper, Rock, Scissor

4. There is no reliable way with

such a low CD4 count


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QuantiFERON-TB Gold (QFT-G) 4-drug therapy

  • FDA approved May, 2005

  • Whole blood test to screen for LTBI and active TB

  • ELISA test detects release of interferon-gamma from sensitized person

  • QFT-G represents one type interferon-g release assay (IGRA)


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Stage 1 Whole Blood Culture 4-drug therapy

Nil

Control

Avian

PPD

Tb

PPD

Mitogen

Control

Culture overnight at 37oC

TB infected individuals respond by secreting IFN-g

Transfer undiluted whole blood

into wells of a culture plate

and add antigens

Heparinized whole blood

Stage 2 IFN-gamma ELISA

COLOR

Standard Curve

TMB

OD 450nm

IFN-g IU/ml

Harvest plasma from above settled cells and incubate 60 min in ‘Sandwich’ ELISA

Wash, add substrate,

incubate 30 min

then stop reaction

Measure OD,

determine IFN-g levels

and interpret test

How Quantiferon™ Is Performed


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In vitro 4-drug therapy

Multiple antigens

No boosting

1 patient visit

Minimal inter-reader variability

Results in 1 day

Stimulate < 12 hrs

In vivo

Single antigen

Boosting

2 patient visits

Inter-reader variability

Results in 2 - 3 days

Read in 48 - 72 hrs

QFT vs. TST


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QuantiFERON-TB Gold (QFT-G) 4-drug therapy

  • Per the CDC…

  • Can be used like TST

  • Response is unique to Mtb, Mkansasii

  • Useful in BCG vaccinated persons

  • No confirmatory test for LTBI

  • Probably more specific than sensitive


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HIV and TB Drug-Drug Interactions 4-drug therapy

Subtitled….

The ongoing dilemma of rifamycins and ARV interactions

Or

When are the PI manufacturers going to start supplying Rifabutin to the world? (and when is the cost of rifampin and rifabutin going to drop?)


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Life in Trinadad 4-drug therapy

29 yr old pregnant woman with previous Rx with triamune (Bonus Question).

CD4 45 and smear positive TB for the 2nd time.

Your treatment options include:

  • TB only

  • HIV only

  • TB for a while, then add on HIV


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Life in Trinadad 4-drug therapy

Your TB choices are:

RIPE only with R=Rifampin

Your HIV choices are:

AZT, DDI, D4T, 3TC, EFV, NVP, Kaletra


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HIV and TB 4-drug therapyDrug-Drug Interactions

  • NRTIs and NRSI okay

  • NNRTI and PIs some interaction due to liver metabolism

  • If only rifampin available, limited choices of ARV medications


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HIV and TB 4-drug therapyDrug-Drug Interactions

  • Rifampin-based regimens:

    • Ritonavir (600 mg bid) + Normal dose Rifampin (600 mg)

    • Efavirenz (inc 800 mg daily) + usual dose Rifampin (600 mg)

      That was it in 2004 and still it in 2006

Burman and Jones. AJRCCM 2001;162:7


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TB and HIV Co-Morbidities 4-drug therapy

  • Important to treat active TB before starting HAART, but may start right after

  • Drug interactions limit choices of HAART if on TB therapy

  • Strongly consider routine preventive therapy for LTBI in all HIV infected persons. (No…Hep C not a contraindication).

Burman and Jones. AJRCCM 2001;162:7


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