TITLE

TITLE

https://www.livescience.com /42937-photo-tuberculosis-b acteria.html Antiretroviral Therapy & Tuberculosis Eth el D . Weld, MD , Ph. D [email protected] July 21, 2019 IAS Mexico City https://kashpersky.com/humanimmunodeficiency-virus Global burden of TB disease In 2014, TB surpassed HIV as the #1 infectious disease killer worldwide High TB burden among people with HIV 20 times more likely to get TB dz Annual #s (2017) Total Population

People with HIV Incidence 10.0 million 900,000 (9%) Deaths 1.3 million 300,000 (23%) TB is estimated to have killed 1 in 7 of humans who have ever lived 1 in 3 deaths of people living with HIV are from TB WHO Global Tuberculosis Report 2018: http://www.who.int/tb/publications/global_report/en/; https://www.unaids.org/sites/default/files/media_asset/tb-and-hiv_en.pdf Logo here Case # 1 A sixty-six year old Scandinavian sailor with history of depression/suicidality presents from cargo ship with chills, dyspnea, and feeling freezing cold 66-yo Scandinavian sailor with history of

depression presents from cargo ship w/ chills, dyspnea, cough, and feeling freezing cold Initial presentation 4/7 VS: T 38.4 HR 105 RR 35 BP 72/40 SaO2 82% on 100% non-rebreather Coarse crackles bilaterally; purplish skin lesions; benign abdomen; no edema Admitted to ICU, intubated 4/8 Chest CT 4/7 CXR (AP) 66-yo Scandinavian sailor with history of depression presents from cargo ship w/ chills, dyspnea, cough, and feeling freezing cold Initial presentation 4/7 VS: T 38.4 HR 105 RR 35 BP 72/40 SaO2 82% on 100% non-rebreather Coarse crackles bilaterally; purplish skin lesions; benign abdomen; no edema Admitted to ICU, intubated, TMP-SMX 15 mg/kg/day + prednisone 60mg PO qday begun 4/11 Rapid HIV 1/2 Ab/Ag test + HIV-1 RNA PCR 91,500 copies/ Minimal improvement; TB concern arises mL

CD4 = 2 (0.6%) 4/11 Bronchoscopy: +Pneumocystis jirovecii Skin biopsy: +Kaposis sarcoma 4/8 Chest CT 4/7 CXR (AP) Question 1: What is the quickest & best way to diagnose active TB in PLWH w CD4 <100? A. B. C. D. Test Name Interferon-Gamma Release Assay (IGRA) Tuberculin skin testing (PPD) with anergy testing Sputum smear/ culture Urinary Lateral Flow Liparabinomannan (LAM) Antigen Question 1: What is the quickest & best way to diagnose active TB in PLWH w CD4 <100? A. B.

C. D. Test Name Interferon-Gamma Release Assay (IGRA) Tuberculin skin testing (PPD) with anergy testing Sputum smear/ culture Urinary Lateral Flow Liparabinomannan (LAM) Antigen Urine Lipoarabinomannan (LAM) Ag Test LAM Ag=LPS in mycobacterial cell walls Released from active or degenerating bacilli Only present in people w active TB LF LAM Ag test Apply 60 L urine to test strip Incubate at room temp 25 mins, inspect with eye Pooled sensitivity 56%; pooled specificity 90% (CD4 <100) [WHO (2015) The Use of lateral flow urine LAM for the diagnosis and screening of active tuberculosis in people living with HIV https://www.who.int/tb/ publications/use-of-lf-lam-tb-hiv/

Comparative & Combined Sensitivity Xpert + LAM 85% Xpert 76% LAM 49% Shah M. et al, AIDS, 2014 IAS Amsterdam, 2018 tell your government a life is worth at least the price of a $3.50 LAM test Photograph courtesy of R. Chaisson Further Laboratory Data 4/11 urinary LF-LAM: positive 4/11 bronchial wash: AFB smear positive; culture: +MTb. 4/18 sputum: AFB smear +, AFB culture positive MTB, Gene Xpert: rifampin-sensitive Mtb (no rpoB) Question 2: How should you time the HIV drugs and the TB drugs? A.

B. C. D. E. Options Start both now Start TB drugs now, HIV Start TB drugs now, HIV Start HIV drugs now, TB Start HIV drugs now, TB drugs drugs drugs drugs within 2 weeks after 6 months in 2 weeks in 6 weeks Timing of Initiation of ART for Patients with TB and HIV In patients with CD4+ Abdool Karim S et al. (2010) NEJM 362: 697 T-cell counts of less than 50 per cubic millimeter,

earlier ART was associated with a rate of AIDS or death that was about two thirds lower than the rate with later ART WHO guidelines recommend waiting 28 weeks after the initiation of antiTB therapy to initiate ART, TB therapy to initiate ART, in patients who are not yet receiving ART, & ART initiation within 2 weeks for patients whose CD4+ cell count is <50 cells/mm3 Question 2: How should you time the HIV drugs and the TB drugs? A. B. C. D. E. Options Start both now Start TB drugs now, HIV Start TB drugs now, HIV Start HIV drugs now, TB Start HIV drugs now, TB

drugs drugs drugs drugs within 2 weeks after 6 months in 2 weeks in 6 weeks Question 3: What is the best treatment option of those listed? B. TB treatment (rifamycin plus HZE) Rifampin 600 mg daily (standard dose) Rifampin standard dose C. Rifabutin 150 mg thrice weekly D. E. F.

Rifampin standard dose Rifampin standard dose Rifampin standard dose A. HIV treatment (plus 2 NRTI) Efavirenz Darunavir/ritonavir 1600/200 daily Lopinavir/ritonavir standard dose Raltegravir 800mg twice daily Dolutegravir 50mg once daily Dolutegravir 50mg twice daily TB treatment (rifamycin plus HZE) HIV treatment (plus 2 NRTI) A. Rifampin Efavirenz

B. Rifampin DRV/r double dose C. Rifabutin 150 mg thrice weekly LPV/r D. Rifampin RAL 800 BID E. Rifampin DTG qday F. DTG BID Rifampin A. Avoid EFV given hx depression/suicidality B. Boosted PI concentrations diminished >90% when given with rifampin

-super boosting to achieve mg to mg parity (kids) -double dosing in adults (gradual increase) -DRV/r trial [CROI 2019]: Double dose or BID + RIF proved quite toxic C. RBT plus boosted PI: Bidirectional drug interactions Dose reduce to thrice weekly More recent PK data: LPV/r BID+ RBT 150 MWF subtherapeutic RBT concentrations relapses w RIF-resistant MTB US guidelines: 150mg qd w boosted PI Limited safety data D, E. Why do RAL when you can do DTG? Higher barrier to resistance, more potent Question 3: What is the best treatment option of those listed? B. TB treatment (rifamycin plus HZE) Rifampin 600 mg daily (standard dose) Rifampin standard dose C. Rifabutin 150 mg thrice weekly

D. E. F. Rifampin standard dose Rifampin standard dose Rifampin standard dose A. HIV treatment (plus 2 NRTI) Efavirenz Darunavir/ritonavir 1600/200 daily Lopinavir/ritonavir standard dose Raltegravir 800mg twice daily Dolutegravir 50mg once daily Dolutegravir 50mg twice daily Do we need to adjust EFV dose w TB treatment? RIF EFV

CYP 2B6 EFV Cmin 8-OH EFV EFV with RIF EFV alone INH CYP 2A6 7-OH EFV ACTG Trial A5221 EFV PK Substudy, N= 543 1 g/mL RIF PK TB-Rx No TB-Rx Cmin (ng/ mL)* 1.96

(1.24-3.79) 1.80 (1.26-2.63) *Median (IQR) Luetkemeyer et al. Clinical Infectious Diseases (2013) 57: 586. Can we give double dose DRV/r w RIF? All 5 ppts w grade 3 or 4 ALT were symptomatic Ebrahim I et al. Pharmacokinetics and safety of adjusted darunavir/ritonavir with rifampin in PLWH. CROI 2019. Seattle. 47 March 2019. Oral abstract D T G c o n c e n tra tio n (u g /m l) Dolutegravir BID Dosing with Rifampicin * DTG DTG DTG DTG DTG 7 6

50mg 50mg 50mg 50mg 50mg QD BID BID BID + RIF BID + RIF 5 4 DTG 50mg twice daily w RIF 600mg well tolerated Similar troughs to DTG 50mg daily without RIF 3 2 1 0 0 4

8 12 16 20 24 hours Error bars represent standard error *Healthy volunteers Dooley K et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. JAIDS 2013 Jan 1;62(1):21-7. Virologic and Immunologic Results in the ITT-E Population in INSPIRING trial Percentage, % Modified FDA Snapshot Analysis (ITT-E) Proportion of participants with HIV-1 RNA <50 copies/mL (95% CI) 100 82 (95% CI: 70, 93) 80

60 75 (95% CI: 65, 86) INSPIRING pharmacokinetic data Pre-dose concentration: DTG 50 mg BID with RIF-based TB treatment Time n DTG CT (ng/mL) geometric mean (%CVb) Week 8 42 870 (118) Week 24 23 964 (263) Pre-dose concentration: DTG 50 mg QD (post-TB treatment phase)

40 20 0 DTG (n=69) EFV (n=44) 0 4 8 12 16 20 24 28 32 36 40

44 48 n DTG CT (ng/mL) geometric mean (%CVb) Week 36 27 854 (208) Week 48 26 881 (281) DTG Ctau, when administered twice daily with RIF, was similar to DTG 50 mg once daily without RIF and to previously reported data for DTG 50 mg once daily in phase II/III HIV trials -20 -4 Time

52 Week Dooley KD et al, Clinical Infectious Diseases, (April 2019) https://doi.org/10.1093/cid/ciz256. TAF-FTC (25mg/200mg) qDay with RIF 600mg FTC unaffected; plasma TAF exposures are lowered 55% Geometric mean ratios (90% CI) of plasma TAF Cmin with and without RIF 0.45 (0.42-0.50) Geometric mean ratios (90% CI) of plasma TAF AUC0-24 0.46 (0.400.52) However, intracellular TFV-DP concentrations only decrease by 36% still 4-fold higher than intracellular concentrations achieved by standard TDF It is likely this will achieve clinical effect This remains to be tested Cerrone M, Alfarisi O, et al, Journal of Antimicrobial Chemotherapy, Volume 74, Issue 6, June 2019, Pages 16701678 HIV-TB Co-Treatment: Recent adult trials Treatment of TB Disease Antiretroviral medication Efavirenz Lower-dose efavirenz

Rifamycin* High-dose rifampicin Rifampicin Raltegravir Rifampicin Dolutegravir Ritonavir-boosted lopinavir Ritonavir-boosted darunavir Rifampicin Rifabutin Riafmpin Rifampin Tenofovir alafenamide (TAF) Rifampicin Trial name/sponsor RIFAVIRENZ/ ANRS 12 292 ENCORE-1 substudy OPTIMIZE project REFLATE/ANRS 12 180 INSPIRING/ViiV

ACTG A5290 Ebrahim et al, CROI 2019 Gilead Sciences Dose adjustments in adults Probably none (600mg EFV +RIF still suppressed VL; C24,AUC down 17%, 13%) Likely not necessary Increase raltegravir to 800 mg twice daily (standard dose still suppressed VL) Increase dolutegravir 50 mg twice daily Decrease rifabutin to 150 mg once daily Double-dose r/LPV (better tolerated) 1600/200 qday & 800/100 BID (not tolerated) Increased TAF Likely not necessary Atwine et al IAS 2017 MOPEB0340 Poster; NCT01986543; Cerrone 2019 CID and Kaboggoza 2019 Open Forum Inf Dz ; Grinsztejn et al Lancet ID 2014 14:459; Clinical Infectious Diseases 2019 (in press); in preparation (see also Naiker 2014; Lan 2014); Cerrone M et al, Journal of Antimicrobial Chemotherapy, Volume 74, Issue 6, June 2019, Our patient 6/5: methylprednisolone begun for IRIS 4/11 RHZE initiated*

4/25: ART initiated Dolutegravir 50mg po BID TDF 300mg daily/ Emtricitabine 200mg daily HIV VL 91K (4/10)266K (4/25)237 (5/27) 55 (6/13) *standard dose RIF 600mg po qday Had progressive respiratory failure and passed away 6/14 Logo here Case # 2 Pa t i e n t On e s sh i p m a te p re s e n t s because she too is HIV+ (VL <20 c o p i e s / m L ; C D 4 5 6 0 , o n D T G / T D F / F TC ) and in a contact tracing she has been found to have positive PPD. She is asymptomatic with negative CXR.

Question 4: His shipmate has HIV (on DTG/TAF/FTC) & new positive Tuberculin Skin Test. She spends long periods of time at sea w/o access to care; requests a short course. What advice do you give her? Options A. No need for treatment for latent TB infection (LTBI); ART is sufficient to prevent TB disease in patients with HIV infection B. Take isoniazid preventive treatment (IPT) for 6 months C. Take a 12-dose, once-weekly treatment with INH and RPT D. Take rifampin daily for 4 months E. Take one month of daily INH and RPT START: Immediate vs Deferred ART for HIV+ w CD4 >500 Immediate ART (n = 2326) Endpoint Deferred ART (n = 2359) HR (95% CI) P Value N

Rate/100 PY N Rate/100 PY Serious AIDS-related event 14 0.20 50 0.72 0.28 (0.15-0.50) < .001 Serious non-AIDSrelated event 29 0.42 47

0.67 0.61 (0.38-0.97) .04 All-cause death 12 0.17 21 0.30 0.58 (0.28-1.17) .13 Tuberculosis 6 0.09

20 0.28 0.29 (0.12-0.73) .008 Kaposis sarcoma 1 0.01 11 0.16 0.09 (0.01-0.71) .02 Malignant lymphoma 3 0.04

10 0.14 0.30 (0.08-1.10) .07 Non-AIDSdefining cancer 9 0.13 18 0.26 .09 CVD 12 0.17 14

0.20 0.50 (0.22-1.11) 0.84 (0.39-1.81) INSIGHT START Group. N Engl J Med. 2015; 373:795-807]. .65 Probability of death in the Temprano Study IPT reduces risk of death by 37% independent of ART Badje et al., Lancet Global Health, 2017 Cumulative probability of tuberculosis 0.05 0.10 0.15 0.20 0.25 IPT reduces risk of TB disease in PLWH irrespective of ART

Did not start IPT 0.00 Started IPT Rio de Janiero HIV+ TST+ IPT x 6 months 1 mo Number at risk (events) Did not start IPT Started IPT 1222 732 1 yr (58) (7) 400 1470

2 yr (14) (12) 318 1506 3 yr 4 yr Years since PPD+ (9) (12) 241 1437 (1) (2) 168 1149 5 yr (2) (5)

123 790 6 yr (2) (3) 84 414 7 yr (0) (0) 62 189 Golub et al., CID, 2015 Am J Respir Crit Care Med 2006;178:922-6. 3HP- Once-weekly rifapentine + INH (900/900mg) x 12 doses 3HP

9H Efficacy 0.39/p-y 1.25/py Treatment completion 89% 64% Drug d/c from hepatotoxicity 1% 4% Subgroup Analysis among PLWH [Sterling et al, AIDS 2016] 3HP: more likely to be completed, non-inferior or superior in efficacy, and less likely to cause toxicity than 9H in adults, adolescents and children >2 years 3HP vs 9H in HIV+ People in PREVENT TB Study (TBTC 26)

All study participants, mostly HIV negative HIV+ participants w supplemental enrollment Log-rank P=0.06 3HP consistently better than 9H Sterling et al., NEJM 2011,365:2155-66 Sterling et al., AIDS 2016,30:1607-15 ARVs which can be coadministered with 3HP Can be coadministered w/o dose adjustment: tenofovir disoproxil fumarate (TDF) emtricitabine efavirenz raltegravir dolutegravir Questions Remain: TAF + 3HP? TAF + 1HP? TAF+ RIF in HIV-TB DTG + 3HP in

treatment nave? DTG + 1HP? 1HP in childhood and pregnancy Sanofi, 2015; Podany AT et al. Clin Infect Dis. 2015 Oct 15;61(8):1322-7; Weiner M, et al. J Antimicrob Chemother. 2014 Apr;69(4):1079-85. DOLPHIN: DTG and 3HP in patients with HIV Study design Design: Single-arm Phase I/II PK and safety study of DTG-based ART and onceweekly rifapentine plus isoniazid (3HP) in adults with HIV infection on ART with suppressed viral load who have indication for treatment of LTBI Timeline: DTG 50 mg QD + TDF/FTC daily x 8 weeks (EFV washout) DTG 50 mg QD + TDF/FTC daily + HP weekly x 12 weeks Regimens: Group 1A: DTG 50mg QD + TDF/FTC +3HP (900/900) interim analysis Group 1B and 2: DTG 50 mg QD + TDF/FTC + 3HP Sample size: 60 (30 in Group 1 (12 in 1A, 18 in 1B), 30 in Group 2) *DTG dose adjustment deemed unnecessary after interim analysis Dooley, et al., CROI 2019, LB37

Dolutegravir with 3HP Study Day 57/58 59 72 73 74 78 108 109 Week on 3HP N Day Post HP Dose Geometric mean Troughs, 5 and 95th % Regimen

Change in AUC (n=60) th Week 1 60 30 0 1 1003 1053 500 -2080 412 - 1834 DTG alone DTG+HP Week 2 Week 3 Week 3 Week 3 Week 8 Week 8

30 60 60 30 60 60 7 1 2 6 1 2 492 657 355 388 703 394 200-1063 295-1502 134-933 140 - 794 289 - 1603 121 - 1079

DTG+HP DTG+HP DTG+HP DTG+HP DTG+HP DTG+HP *HP doses were given on Days 58, 65, 72, 79, 86, 93, 100, 107 Delta AUC week 1 +16% (75) Delta AUC week 3 -29% (23) Delta AUC week 8 -29% (27) Viral load < 40 copies/mL at Baseline, Week 9 (DTG+HP) in all participants One participant with VL = 2,300 copies/mL at Week 24 (4 weeks post-HP); following adherence counseling, on

recheck VL < 40 copies/mL Dooley, et al., CROI 2019, LB37 LTBI Treatment Guidelines WHO 2018 Rifapentine and isoniazid weekly for 3 months may be offered as an alternative to 6 months of isoniazid monotherapy as preventive therapy for both adults and children in countries with a high TB incidence (Conditional recommendation, moderatequality evidence. New Recommendation) Remark: Rifampicin- and rifapentine-containing regimens should be prescribed with caution to people living with HIV who are on ART because of potential drug-drug interactions In settings with high TB incidence and transmission, adults and adolescents living with HIV who have an unknown or a positive TST and are unlikely to have active TB disease should receive at least 36 months of IPT, regardless of whether they are receiving ART. http://apps.who.int/iris/bitstream/handle/10665/260233/978924550239eng.pdf;jsessionid=01FC4B448B5BE575BBC0C1421FD14724?sequence=1 Updated CDC recommendations for once-weekly isoniazidrifapentine for 12 weeks (3HP) for LTBI treatment (June 2018) Updated ART guidelines (July 2018 ) CDC continues to recommend use of the short-course combination regimen of once-weekly isoniazid-rifapentine for 12 weeks (3HP) for treatment of latent tuberculosis infection (LTBI) in adults. With regard to age limits, HIV infection, and administration of the treatment, CDC now also recommends the following:

use of 3HP in persons aged 217 years; use of 3HP in persons with LTBI who are living with human immunodeficiency virus (HIV) infection, including acquired immunodeficiency syndrome (AIDS) and taking antiretroviral medications with acceptable drug-drug interactions with rifapentine* *efavirenz or raltegravir https://www.cdc.gov/mmwr/volumes/67/wr/mm6725a5.htm?s_cid=mm6725a5_w http://www.who.int/hiv/pub/guidelines/ARV2018update/en/ Stay tuned for guidelines to follow 36 Question 4: His shipmate has HIV (on DTG/TAF/FTC) & new positive Tuberculin Skin Test. She spends long periods at sea w/o access to care; requests a short course. What advice do you give her? Options A. No need for treatment for latent TB infection (LTBI); ART is sufficient to prevent TB disease in patients with HIV infection B. Take isoniazid preventive treatment (IPT) for 6 months C. Take a 12-dose, once-weekly treatment with INH and RPT D. Take rifampin daily for 4 months E. Take one month of daily INH and RPT

BRIEF TB Time to endpoint, by CD4 Time to endpoint for all ppts Events/PY Incidence per 100 PY 1HP 32/4926 0.65 CD4 <250 9H 33/4896 0.67 CD4 >250 Efavirenz-based ART permitted while on RPT/INH. Swindells S, NEJM March 2019 Acknowledgements Maunank Shah Mauro Schecter

Kelly Dooley David Back Dick Chaisson Katie McAllister Clinical Pharmacology Division, Infectious Disease Division, JHU SOM Johns Hopkins Center for TB Research Johns Hopkins University Center for AIDS Research (CFAR) P30AI094189 Johns Hopkins Clinical Research Scholars KL2 Award Pearl M. Stetler Research Award for Women Physicians NIH T32 GM066691-11 & GM066691-12, NIGMS Extra Slides HIV ASSIST: www.hivassist.com Useful online educational tool for HIV treatment decision support leveraging several databases (incl. Liverpool DDI!) to generate prospective ART regimens, weighted and ranked by utility IAS 2019: Poster MOPEB228 Retrospective cohort validation study of tool Monday July 22 12:30-14:30 HIVASSIST: www.hivassist.com

Exposure-response for rifampin Dose-response in mouse model Early Bactericidal Activity in smearpositive pulmonary TB patients Rifampin is currently dosed at the low end of the therapeutic spectrum Jayaram et al, AAC (2003); 47:2118; Diacon et al, AAC 2007; 51(8) Slide courtesy of Maunank Shah EFV dose: 400mg vs 600mg ENCORE Study Adverse event related to EFV: 126 (39%) for EFV 400 mg 148 (48%) for EFV 600 mg (p=003) % w C12 < 1 mg/L: 14 (5%) for EFV 400mg 1 of 14 w VL >20 copies/mL Non-inferiority comparisons at week 48 for VL< 50 copies/mL 6 (2%) for EFV 600mg EFV levels lower in 400mg 3 of 6 w VL> 20 copies/mL group, but dose did not affect virologic response Carey D et al, Lancet Infect Dis. 2015 Jul;15(7):793-802.

RIFAVIRENZ Trial EFV 600mg or 800mg + high-dose RIF 20 mg/kg in people w HIV-TB Atwine D, et al, Efavirenz pharmacokinetics with rifampin double dose in TB-HIV infected patients. 25th Conference on Retroviruses and Opportunistic Infections. March 5, 2018. Boston. Abstract #456. EFV 400mg + INH/RIF in PLWH without TB Geometric Mean Ratio (90% CI) C24hr (ng/mL) PK2/PK1 PK3/PK2 PK3/PK1 .85 (.72-.99) .88 (.751.03) .75 (.62.92) EFV 400 mg once daily (PK1) 4 weeks EFV/INH/RIF (PK2)

12 weeks EFV/INH/RIF (PK3) 800 ng/mL EFV concentration cutoff Cerrone M, et al. Pharmacokinetics of Efavirenz 400 mg Once Daily Coadministered With Isoniazid and Rifampicin in Human Immunodeficiency Virus-Infected Individuals. Clin Infect Dis. 2019 Jan 18;68(3):446-452. doi: 10.1093/cid/ciy491. Drug-Sensitive TB: The Role of Individual Drugs INH: Early bactericidal activity, rapid reduction in organism burden Rifampin: Unique sterilizing activity against persisters, key contributor to cure without relapse Pyrazinamide: Sterilizing activity in cavities/acidic environments over the first 2 months, enabling shorter treatment Ethambutol: Prevents resistance to other antibiotics Slide courtesy Kelly E. Dooley

Principles of Antimycobacterial Chemotherapy TB disease: metabolic & anatomic compartments Metabolic state of bacteria may vary by lesion type Need for prolonged therapy (months) to completely eradicate infection (because of persisters) Drug activity may be different depending on microenvironment TB is both an intracellular and extracellular disease http://www.nature.com/nrmicro/journal/v1/n2/images/nrmicro749-f1.jpg 50 Adult trials (DS-TB) TB Research Area Drug-sensitive TB Treatment shortening Key studies in Adults HIGHRIF1: Rifampin max tolerated dose (max 40 mg/kg) HIRIF: Higher-dose rifampicin (max 1200) RIFASHORT: Higher-dose rifampicin (to 1800), 4 months

MAMS-TB-01: High-dose rifampicin +/- moxifloxacin Phase II II III II Status Completed Completed Enrolling Complete TBTC 31/A5349: High-dose RPT +/- moxifloxacin III Fully enrolled IIC Planning

Optimizing rifamycins SUDOCU (PanACEA): BDM+STZ vs. R HZ E vs. R HZE vs. SOC high high high Regimens involving new drugs SimpliciTB: BDQ+Pretomanid+MFX+PZA, 4 months APT: pretomanid+INH+PZA+RBT or RIF, 12 weeks TRUNCATE-TB: multiple 2 month regimens Clo-FAST (ACTG A5362): Clofazimine + RPT+ HZE, 13-17 weeks CRUSH-TB (TBTC): BDQ+MFX+PZA+ RBT or DLM, 4 months III II

III IIC IIC Enrolling Enrolling Enrolling Planning Planning Key: MFX=moxifloxacin, PZA=pyrazinamide, INH=isoniazid; RBT=rifabutin; RIF=rifampin; BDQ=bedaquiline; RPT=rifapentine; DLM=delamanid Slide courtesy KE Dooley Worse treatment outcomes w treatment shortening for TB with HIV Imperial M. et al., A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis, Nature Medicine 24, 17081715 (2018) But! TB-HAART study Concurrent defined as starting ART within 2 weeks of the start of pulmonary TB therapy Concurrent HIV and TB treatment not necessary

for patients with CD4 count > 220 cells/mm3? N.B. Our patients CD4 is 2 Note: ART regimen was a combo of AZT, 3TC, & EFV Mfinanga et al Lancet ID 2014

Recently Viewed Presentations

  • Grade 12 Parent information night - Holy Trinity Catholic ...

    Grade 12 Parent information night - Holy Trinity Catholic ...

    HT's deadline for OUAC - Prior to Christmas Holidays. January 15th - DEADLINE to apply to OUAC. Feb, April, July - marks to Universities . www.electronicinfo.ca. Campus visits. We believe a campus visit is essential when deciding which post-secondary institution...
  • Jonathan Swift

    Jonathan Swift

    Jonathan "Isaac Bickerstaff" Swift (1667-1745) Biography Born November 30, 1667 Trinity College, Dublin Secretary of Sir William Temple, taught his daughter Esther Johnson Went to Oxford 1692 Became a priest 1694 Doctor's degree at Dublin 1701 Married Stella Published, anonymously,...
  • Point Groups - University of California, Irvine

    Point Groups - University of California, Irvine

    1. Determine point group of molecule (if linear, use D 2 h andC 2 v instead of D ∞ h or C ∞ v) 2. Assign . x, y, z. coordinates (z. axis is principal axis; if non-linear, y. axes...
  • Optimizing Modular Multiplication for NVIDIA's Maxwell GPUs by

    Optimizing Modular Multiplication for NVIDIA's Maxwell GPUs by

    Optimizing Modular Multiplication for NVIDIA's Maxwell GPUs. by. Niall Emmart. 1, Justin Luitjens. 2, Charles Weems. 1. and Cliff Woolley. 2. 1 . University of ...
  • Ch. 12

    Ch. 12

    Realms of existence radiate out from the center. The 3-d mandalas were represented in architecture (as a building form - see Borobadur) Provided a fixed, empowered, sacred space that a person or monk could walk into the space and move,...
  • Temporally precise in vivo control of intracellular signaling ...

    Temporally precise in vivo control of intracellular signaling ...

    Used an Optrodeto measure multiunit in vivo neuronal firing. No differences of firing rates between dark and photo-stimulated cells . opto-β 2. AR transfected cells showed decreased network firing when stimulated (supports current research)opto-a 1. AR transfected cells showed increased...
  • Rensselaers Sustainability Charrette Environment  Economics  Education Envision  Explore

    Rensselaers Sustainability Charrette Environment Economics Education Envision Explore

    Operations - Defined. Operations at Rensselaer involves all day to day activities that impact the learning and living environment of Rensselaer students, faculty, and staff. Specific areas include building maintenance and cleaning, upkeep of lawn and garden areas, operation of...
  • WELCOME BACK Iowa Educational Services for the Blind

    WELCOME BACK Iowa Educational Services for the Blind

    Target. Increase to 100% the students who have transition goals and outcomes in place by age 16 including appropriate measurable postsecondary goals that are annually updated and based upon an age appropriate transition assessment, transition services, including courses of study,...