Challenges of TB/HIV in the region

Alicia Piñeirúa Menéndez, MD, MPH

Bogotá, April 5th, 2019

Agenda

• Burden of the dueto: regional data

• Latent tuberculosis

• Diagnostic challenges and new diagnostic tools

• Tuberculosis treatment, susceptible, MDR and special situations

• ARV’s + TB: IRIS, drug-drug interactions

• Final messages

HIV-TB Burden: Regional data

• 11% HIV/TB co-infection; 16% preventive therapy

• Funding sources: 66% domestic funding, 22% unfunded, 12% international

PAHO/WHO Tuberculosis in the Americas, 2018

HIV-TB burden: regional data

20 countries with highest TB burdens, absolute numbers of incident cases86,858 tb cases were reported during 201713% HIV/TB co-infected9.5% MDR TB: only 1.5% new cases, 8% previously treated85% domestic funding, 15% unfunded

40 countries with highest MDR TB ratesHighest burden of MDR tuberculosis cases in the region1366 cases of MDR TB by 2015, 104 cases of XDR TBIncreasing success of XDR treatments (66%) and decreased LTFU’s (27% to 2%)

Alarcón, INT J TUBERC LUNG DIS, 2017Global Tuberculosis Report, WHO, 2018

Tuberculosis in Latin America

Factors associated to TB incidence:

• HIV/TB co-infection

• Multidrug resistant TB

• Basic sanitation

• Water coverage

Factors associated to TB mortality:• Literacy among women

• Multidrug resistant TB

• Basic sanitation

• Indigenous population

• Nutritional status

Bergonzoli et al, Pan American Journal of Public Health, 2016

The path to End TB. . .

2030:90% reduction in TB related deaths 80% reduction TB incidence

End TB

Social determinants

Diagnosis: clinical challenges and available tools

Drug availability

HIV co-infection

MDR TB

Latent tuberculosis infection (LTBI)

Uncertain global burden. 1/3 of the global population estimated to be infected with M tuberculosis.

5-10% HIV negative will develop TB- lifetime. HIV+ population: 15% annual risk of developing active TB (21 times more likely to develop active TB than HIV-)

Latin America data:

• Migrant population

US/Mexico border:+ IGRA: 50% +TST: 34%; 71% concordance

Spain LA migrants: + TST: 32.1%

Am J Trop Med, 2015Oren et al, BMC infectious diseases, 2016

Houben, PLOS medicine, 2016

LTBI: high burden approach

INH regardless IGRA/ TST results.

Rangaka, Lancet, 2014Temprano ANRS 12136 Study Group, NEJM, 2015

Badje Lancet Global Health 2017

2ble blind, RCT, IPT/PBO x 12 months, stratified by ART status37% reduction of TB incidence

RCT. IPT for 6 mo +/- immediate deferred ART.IPT+Immediate ART: 44% of reduction in any severe HIV related illness and 35% reduction in death any cause

LTBI: low burden approach

• Based on latent TB diagnosis

- Recommendations:

* BHIVA: IGRAS over TST. WHO: either TST or IGRA

Treatment options:

IGRA/TST availabilityINH availability in Latin America

BHIVA TB/HIV Co-infection Guidelines 2017Menzies, NEJM, 2018

Sterling, AIDS, 2016 Swindells, LB37, CROI, 2018

Treatment Time

Isoniazid Daily, 6 / 9mo

Rifapentin + Isoniazid Daily, 3 mo

Isonazid + Rifampin Daily, 3 mo

Rifapentin + Isoniazid Weekly, 3 mo

Rifampin Daily, 3-4 mo

Tools for TB diagnosis

The challenges: Rates of extrapulmonary diseaseSmear negative pulmonary disease Minimal/no findings in X ray

The classics: Smear microscopy: 50%S for HIV neg, 26% for HIV+

Culture: 7-28d. MGIT 71-98% (3 samples $$, availability)

Harries, Diagnostics, 2018

Mac Lean, Curr Opin HIV/AIDS, 2018

LA region: 40% of definite TB diagnosis,

35.6% probable, 24.5% presumptive

Efsen, PlosOne, 2015

Tools for TB diagnosisGenexpert.- Sens: 97% (smear

positive) and 71% (smear negative); 79% overall Spec: 98%

GeneXpert ultra.- software upgrade, detects bacili at a lower threshold (WHO recommendation, 2017) CSF samples: S= 90%

New cartridge identifying H, FQ (S:<90%) and aminoglycosides (S:70%) resistance

GeneXpert edge.- portable, POC geneXpert

Mac Lean, Curr Opin HIV/AIDS, 2018

Harries, Diagnostics, 2018

Tools for TB diagnosis

Urine lipoarabinomanan (LAM)Sensitivity depending on CD4+ cell count: S: 39% <200 cel/mm3, 51.7%: <100 cel/mm3, 66.7: <50 cel/mm3 Specificity: >95%

Mac Lean, Curr Opin HIV/AIDS, 2018Gupta Wright, Lancet, 2018

STAMP trial: Smear + GeneXpert (SOC) vs Smear+ GeneXpert + LAM (Intervention) all hosp admissions

Adjusted risk difference

Overall mortality -2.8 (-5.8 to 0.3)

<100 CD4+ cell count -7.1 (-13.7 to -0.4)

Hb < 8 g/dl -9.0 (-16.6 to -1.3)

Drug susceptibility testing (DST)

• Gold standard: liquid culture, phenotipic DST

• Recommended by WHO in ALL HIV/TB co-infected cases

• New options: GeneXpert, Line Probe Assays (LPA’s)

LPA’s: Genotype MTBDR V1 and V2 (Germany) and NTM and MDRTB Detection (Japan)

Sens Spec

RIF 96.7% 98.8%

H 90.2% 99.2%

HIV 81% 100%

Mac Lean, Curr Opin HIV/AIDS, 2018

LA region: 33.2% isolates tested for DST

Efsen, PlosOne, 2015

Anti tuberculosis treatmentSusceptible TB scenario:

Daskapan et al, Clinical Pharmacokinetics, 2018

R+H+Z+E, daily dosage for 2 months

R+H, daily dosage for 4 (+3*) months

Direct observed therapyAppropriate for pregnancy and

breastfeeding

CNS, Meningitis, OM.- 12 mo

or more

PK of anti-tb treatment in HIV+ population:

Controversial data regarding the effect of HIV on first line anti-tb drugs concentrations-Studies with clinically relevant differences regarding RIF AUC concentrations comparing HIV + vs HIV neg (80% reduction). EMB seems to be also affected especially in pediatric populations-Apparently related to advanced disease.

Drug resistant TB: Recommended regimens

RIFLevofloxacin

PZA ETMB

KanamycinProthionamideHigh dose INH

MoxifloxacinClofazimine

PZA ETMB

Continued

Only intensive phase: variable duration

Levo/Moxifloxacin + Clofazimine+Cycloserine

Linezolid + Bedaquline + Other group C drugs*

*Delamanid/Estreptomycin or Amykacin/ETM/PZA/IMI or MEM/Ethionamide or Prothionamide/PAS.

INH monoresistance MDR short course

MDR long course

Duration of treatment: 18-20 months. Individualise, modify according patients’ response

Duration of treatment: 9-12 months

Duration of treatment: 6 months

WHO MDR TB Guidelines, 2018

Novel strategies for drug resistant TB

• Patients with MDR failing treatment or XDR tuberculosis

Pretomanid 200 mg

BDQ 200 mg TID

Linezolid 600 mg BID

For 6 months

Additional 3 months if sputum + at 4 months

24 wk follow up 75 patients: Interim analysis: 89% favorable outcome50% of participants were HIV + 8 unfavourable outcomes: 6 deaths, 2 relapses

+

+

Conradie et al, The Union Conference/CROI 2017/2018

Other special situations

Koegelenberg et al, SAMJ, 2013

Qiu et al, BMC Infectious Dis, 2019

Renal impairment: adjust drugs according to CrCl when <30 ml/min or HD

Liver impairment: avoid PZA in severe cases. Careful use of Ethionamide, Prothionamide and PAS

Absence of oral route/critically ill patientsAUC for RIF, especially affected (>50% of the cases)Rifampin: only 1st line drug available in IV routeRIF AUC related to higher APACHE, and lower eGFRConsider IV drugs, TDM (dried blood spots?)

Timing of ART initiation: When?• Early (within 2 wks) vs delayed (within 8 wks); impacts mortality among

pts with <50 CD4+ cells/mm3

29% reduction in mortality

<50

>50

Uthman, Annals of internal medicine, 2015

Which ARV to choose? NNRTI’s

AUC change

Action

EFV NS 600 mg QD

NVP 58% Do not co-administer

RPV 80% Do not co-administer

ETV No info Do not co-administer

DOR 85% Do not co-administer

Limited data regarding co-administration of EFV 400 mg + RIF or higher doses of RIF + EFV

Atwine, Br J Clin Pharmacol, 2018Atwine, CROI 2018, Abstract # 456Cerrone, CROI 2018, Abstract 457

Which ARV treatment to choose? INSTI’s

AUC change

Action Studies providing evidence

BIC 75% Do not co-administer 1*

DTG 54% 50 mg BID 1*

EVG No info Do not co-administer 0*

RAL 40% 800 mg BID ¿?/ 400 mg BID 2*

Custodio, CROI 2018, Abstract #34Dooley, IAS conf 2018, Abstract 0206

Grinjzstein, LID, 2014

REFLATE/REFLATE TB2/ INSPIRINGReflate: Phase II:

RIF + EFV 600 mg qd vs RAL

800 mg BID vs RAL 400 mg BID154 patients. Wk 24.- same virological suppression between 3 arms

Reflate TB2:Phase III:

RIF + EFV 600 mg QD vs RAL 400 mg BIDPrimary completion date: Nov 2018460 participants www.clinicaltrials.gov

Dooley, IAS conf 2018, Abstract 0206Grinjzstein, LID, 2014

Inspiring: Phase IIIb:

RIF + EFV 600 mg qd vs DTG 50

mg BID113 patients. Wk 48:Virological supression: 82% (EFV) vs 75% (DTG) Tb cured: 89% (EFV) vs 88% (DTG)

ART experienced patients + NO rifabutin

Ebrahim I et al, CROI 2019, LB 81 Decloedt, PLoS One, 2012 Sunpath, Int J Tuberc Lung Dis, 2014

AUC change Action

ATV/r 72% Switch Rifabutin

LPV/r 75% Switch rifabutin/double dose

DRV/r 57% Do not co-administer

¿DTG? DAWNING BID + RIF?

Tb- associated IRIS• Paradoxical/unmasking

• Very variable incidence.- 4-54%

• Known risk factors: low CD4+ cell count, disseminated tb, early ART initiation

• 2% mortality EXCEPT CNS cases, 25% may require hospitalization

Bana, BMC infectious diseases 2016 Uthman, Annals of internal medicine, 2015

**RCT’s using INSTI’s (REFLATE, INSPIRING, REALITY) did not show increased risk of IRIS comparing INSTI’s vs other regimens

IRIS:PredART trial

• RCT, doble blinded

• HIV/TB diagnosed

• <100 CD4+ cell/mm3

• PDN 40 mg x 14 d followed by 20 mg x 14 d

• 240 patients included

• PDN started within 48 hrs of initiation of ART

Meintjes, NEJM, 2018

IRIS:PredART trial

Meintjes, HIV Conference, Glasgow, 2018

Infectious complications and other OI’s: 33 events in 29 patients. 3 Cryptococcal meningitis 10 Oesophageal candida 7 Sepsis7 Pneumonia1 Pyelobephritis3 C diff infection2 Dysentry

1 SK at wk 28, placebo arm, discontinued ART at wk 20

Deaths: 5 prednisone, 4 placebo (p=1.0)

MDR treatment and ARV DDI’s Metabolised by CYP 3A4. EFV reduces steady state concentration by 52% (model). LPV/r increases BDQ concentrations > 2 fold (monitor QT). No interactions predicted fot NRTI’s, INSTIs or RPV.

LPV/r increased DLM exposure. QTc measurements are needed, may cause prolongation. Contraindicated in hypoalbuminemic patients

(metabolite regulated by serum albumin)

Increased drug adverse events: neuropathy, anemia, optic neuritis, esp with older ARV’s. Consider dose reduction if bone marrow suppression. Risk of

thrombocytopenia may increase with Cr Cl <30 ml/min. Tedizolid/Sutezolid might represent new options.

BDQ

DLM

Linezolid

QuinolonesEffect of EFV-based ART on patients treated with moxifloxacin: AUC reduced by 30%. Further studies needed, no clear clinical implications

Esmail, J Thorac Dis, 2018

Same day ART and TB

•Increases number of people starting ART•Reduces mortality •Reduces MTCT?

•Potential of missing clinical conditions requiring management before ART; risk of IRIS, coertion?•ART should be briefly delayed while investigating for TB among people with symptoms•Caution is needed for PLWH with TB meningitis.- since immediate ART is associated with more severe adverse events

The good: The danger:

It might not be for everyone!!

Final messages

• TB/HIV still a major public health issue in our region, especially in Brazil and Peru

• Many unanswered/partially answered questions: special populations, drug-drug interactions, 2nd

line ARV+ anti tb treatment, MDR and XDR cases• Same day ART might not be for everyone, should

consider ruling out TB before• Public health achievements will largely depend

on actions outside the healthcare sector.-advocate, involve social actors!

Acknowledgements

• Florentino Badial

• Juan Sierra-Madero

• Alexandra Martin-Onraët

Thank you!

aliciapina@yahoo.co.uk