novel regimens for tb prevention: epidemiologic...

Novel Regimens for TB Prevention: Epidemiologic Considerations

C. Robert Horsburgh, Jr, MD, MUS

Boston University School of Public Health

Outline

• Prevention of “Reactivation” TB Disease

• Prevention of Primary TB Disease

• Prevention of M.tb Infection

• Effects of HIV and ART on TB prevention

• Prevention of “Reactivation” TB Disease

J Infect Dis 2011;204:S1160

Natural History of Tuberculosis

Prevention of reactivation in HIV+, TST+ Persons in Rio de Janeiro

CID 2015;60:643

Prevention of reactivation in HIV+, TST+ Persons in Uganda

NEJM 1998;337:805

Prevention of reactivation in HIV+, TST+ Persons in Uganda: Long Term Follow-up

AIDS 2001;15:2141

• Prevention of Primary TB Disease

• Prevention of M.tb Infection

Is longer LTBI Treatment for HIV-infected Persons in Sub-Saharan Africa Better?

HR=0.57, 0.33-0.99

Lancet 2011;377:1593

Is there a Post-treatment Effect?

AIDS 2015;29:356

IPT Effect is not

Discernable under High

FOI Pressure

NEJM 2014;370:301 (Suppl)

• Effects of HIV and ART on TB prevention

Increased Susceptibility of the Exposed HIV-infected Person

In two studies, HIV-infected household contacts (HHC) were more likely to be TST-positive than HIV-uninfected HHC in multivariate analysis

OR = 6.11 (0.89-42)

RR = 2.84 (1.73-4.65)CID 2016;63:10-20

AJRCCM 2016;194:1152-63

Increased Primary TB Disease among HIV-infected Persons

In two studies, HIV-infected household contacts (HHC) were more likely to develop primary TB disease than HIV-uninfected HHC

OR = 8.6 (5.8-13)

RR = 6.94 (3.54-13.6)AJRCCM 2000;162:2033-8

AJRCCM 2016;194:1152-63

Lancet 2001;

358:1687-93

Relapse

and

Reinfection

by

HIV Status

Increased Reactivation TB Diseaseamong HIV-infected Persons

In one prospective cohort study, HIV-infected TST+ homeless persons were more likely to develop TB disease than HIV-uninfected TST+ homeless persons

RR = 9.5 (3.6-25)

AJRCCM 2000;162:460-4

STAGES OF TUBERCULOSIS

HIV -

HIV +

70%

30%

5%

95%

5%

95%

30%

70%

40%

60%

45%

55%

Prevention of TB Disease in HIV+, Anergic Persons in Uganda

AIDS 2001;15:2142

TEMPRANO trial: IPT or ART?

Factorial design comparing early vs. late ART and IPT vs. no IPT

• ART reduced TB, HR = 0.50 (0.32-0.79)

• IPT reduced TB, HR = 0.44 (0.28-0.69)

• TB in ART-/IPT- = 8.0%

• TB in ART-/IPT+ = 3.1%

• TB in ART+/IPT- = 4.2%

• TB in ART+/IPT+ = 2.6%

NEJM 2015;373:808-22

IPT adds to ART

Lancet 2014;384:685

Effectiveness of Oral TB Drugs Against Nonreplicating Bacilli

• Likely highly effective: Rifamycins, Delamanid, Bedaquiline, Linezolid, Clofazimine

• Likely partially effective: Isoniazid, Fluoroquinolones

• Likely ineffective: Ethambutol, Cycloserine,

• Effectiveness unknown: PZA, Ethionamide

Conclusions

• “Latency” is only one of several states that precede TB disease

• Prevention of TB disease can occur by interruption of the natural history of progression at several steps along the pathway

• HIV and ART have strong influence on the ability of the host to drive bacteria into a non-replicating state

• TB drugs have varying efficacy against non-replicating bacilli

novel regimens for tb prevention: epidemiologic...

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