author practical issues of the treatment of by

Interactive cases I:

Practical issues of the treatment of tuberculosis in immunocompromised patients (IRIS and drug Interactions).

Hanif Esmail and Delia Goletti

© ESCMID eLibrary by a

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TB therapy and TB-HIV therapy


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TherapiesTB or LTBI

Full therapy or preventive therapy

HIV

ART


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ART changed the clinical course and outcome of AIDS-related diseases


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ART increases survival in TB patients

Girardi et al, J AIDS 2001


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Initiation of antiretroviral treatment in TB patients living with HIV Recommendation

ART should be started in all TB patients living with HIV regardless of their CD4 cell count (Strong recommendation, high certainty in the evidence).

TB treatment should be initiated first, followed by ART as soon as possible within the first 8 weeks of treatment (Strong recommendation, high certainty in the evidence).

HIV-positive patients with profound immunosuppression (e.g. CD4 counts less than 50 cells/mm3) should receive ART within the first 2 weeks of initiating TB treatment.


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Length of TB treatment in HIV co-infected patients with drug susceptible pulmonary TB

In patients with drug-susceptible pulmonary TB who are living with HIV and receiving antiretroviral therapy during TB treatment, a 6-month standard treatment regimen is recommended over an extended treatment for 8 months or more (Conditional recommendation/very low certainty in the evidence).


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Cytocrome p450


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P450 drug interaction

Rifampicin!

PI inhibitors!


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Preferred regimens for cotreatment of TB and HIV

Tornheim JA, Dooley KE. 2017, Microbiol Spectrum, 2016


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Recommended ART regimens in HIV-TB patients

Swindells, Top Antiviral Med, 2018


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Therapeutic modifications that are required while administering rifamycins and ART concomitantly

Gopalan et al. AIDS Res Ther (2016) 13:34 © ESCMID eLibrary b

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Overlapping toxicities for TB and HIV drugs



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Common overlapping adverse events of first-line anti-TB drugs and antiretroviral drugs

Manosuthi et al. AIDS Res Ther (2016) 13:22


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Dolutegravir and rifampicin: the «INSPIRING» trial

Dolutegravir is a substrate of UGT1A1 and CYP3A4, both of which are induced by rifampicin.

Coadministration with rifampicin results in decreases in dolutegravir plasma exposure, requiring doubling of the daily dose of dolutegravir.

Preliminary results presented at the Conference on Retroviruses and Opportunistic Infectionsof a phase III study (INSPIRING) evaluating the safety of dolutegravir use (50 mg twice daily) in combination with rifampicin.

At 24 weeks, 81% (56/69) of HIV/TB coinfected individuals receiving dolutegravir were shown to have achieved HIV-1 RNA <50 copies/mL

Dooley K, Kaplan R, al MN. Safety and efficacy of dolutegravir-based ART in TB/HIV coinfected adults at week 24. Oral abstract 33. 25th Conference on Retroviruses and Opportunistic Infections. Boston, USA, 2018


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The transition to dolutegravir and other newantiretrovirals in low-income and middle-income countries: what are the issues?

Vitoria et al, AIDS, 2018


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Dolutegravir use in combination with rifampicin-basedtuberculosis therapy: 3 years of real-world experience in a large UK teaching hospital

A case note review of all HIV/tuberculosis (TB) coinfected individuals was conducted between January 2015 and March 2018.

A total of 10 individuals were identified who were on dolutegravir-containing antiretroviral therapy (ART)(dolutegravir 50 mg twice daily) while being treated for TB with rifampicin-based therapy. Six individuals were ART-naive, two had restarted ART having disengaged from care and two switched to a dolutegravir-containing regimen

At baseline, the median CD4 count was 152 cells/mm3 (3–365), and five had a CD4 count <100 cells/mm3. The median HIV-1 RNAwas 5.25 log10 copies/mL, and two treatment-experienced patientswere virologically suppressed on previous ART.

At 24 weeks, 9 of 10 patients had achieved HIV-1 RNA <50 copies/mL.

One patient with well-documented poor adherence had a HIV-1 RNA of 3100 copies/mL at 24 weeks and subsequently resuppressed with improved compliance.

All individuals completed treatment with no recorded grade 3/4 side effects, TB-associated immune reconstitution inflammatory syndrome (IRIS) or discontinuation.

Cevik M, McGann H. Sex Transm Infect 2018;94:420.


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TherapiesMDR-TB or LTBI


HIV

ART


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Bedaquilin and first line TB drugsinteraction

Dheda et al, INT J TUBERC LUNG DIS 20(12):S24–S32

INH

PZA

BDQ+PZA+MXF


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Bedaquilin and second line TB drugsinteraction


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Bedaquilin/delamanid and ART: dugsinteraction

Delamanid is expected not to have any clinically significant interaction with EFV, NVP or boosted PI and can be used concomitantly, as it neither induces nor inhibits the CYP 450 system.


BDQ

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TherapiesTB or LTBI


HIV

ART


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Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug–Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine

This was a single-center, open-label, fixed-sequence, drug–drug interaction study in healthy volunteers.

Four realthy volunteers received oral dolutegravir 50 mg once daily alone (days 1–4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5–19).

Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19.

Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points

Brooks KM, CID 2018


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Neutrophils Lymphocytes

Brooks KM, CID 2018


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Brooks KM, CID 2018


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developed toxicitiy: slowacetylators patients

Decreasedat day 14

Brooks KM, CID 2018


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TherapiesTB or LTBI


HIV

ART


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Preferred regimens for cotreatmentof TB and HIV



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Bedaquilin/delamanid and ART: dugsinteraction

Delamanid is expected not to have any clinically significant interaction with EFV, NVP or boosted PI and can be used concomitantly, as it neither induces nor inhibits the CYP 450 system.


BDQ

=


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Cytokine-Mediated Systemic Adverse Drug Reactionsin a Drug–Drug Interaction Study of DolutegravirWith Once-Weekly Isoniazid and Rifapentine

This was a single-center, open-label, fixed-sequence, drug–drug interaction study in healthy volunteers.

Four realthy volunteers received oral dolutegravir 50 mg once daily alone (days 1–4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5–19).

Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19.

Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points

Brooks KM, CID 2018


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