Preventing TB: Recent Research Results and Novel Short Course Therapy for LTBI Constance A. Benson, M.D. Professor of Medicine Director, UCSD AntiViral Research Unit PI, CD4 Collaborative HIV Clinical Trials Unit University of California, San Diego
Introduction Revised WHO guidelines for LTBI treatment in HIV Evidence base for revisions Obstacles to uptake Impact of antiretroviral therapy on TB prevention Short course alternatives for treatment of LTBI Clinical trials of novel short course regimens TBTC Study 26 ACTG A5279 Where do we go from here?
Risk of Developing Active TB Latent TB Infection (LTBI) Any positive test for LTBI (TST or IGRA) in a person with no clinical, laboratory or radiographic evidence of active TB Risk of active TB in immunocompetent adults: 12.9 per 1,000 person-years (~10% lifetime risk) Highest risk within 2-3 years after index exposure Risk in HIV-infected individuals: After index exposure: 30-40% within 3-6 months Risk of reactivation TB in persons with LTBI (+TST) 35-162 per 1,000 person-years (3-16% per year)
Current Approaches to Tuberculosis Prevention The three (or four) I s Intensified case finding identifying those with active TB, appropriate treatment to reduce infectiousness Isoniazid prophylaxis for treatment of latent TB infection (LTBI) Infection control Initiation of ART (for HIV-infected persons)
Treatment of Latent TB Infection in HIV Infected Persons Review of 12 RCTs of TB preventive therapy in HIV (N=8,578; any anti-tb drugs vs placebo) 32% in incidence of active TB (RR 0.68; 95% CI 0.54-0.85); 62% for TST+ pts (RR 0.38; 95% CI 0.25-0.57) Reduced mortality: INH alone vs. placebo among those with TST+ (RR 0.74, 95% CI 0.55-1.00) INH+RIF vs. placebo regardless of TST (RR 0.69, 95% CI 0.50-0.95) Efficacy similar for all regimens but effect wanes over time Akolo C, et al. The Cochrane Collaboration; 2010
Revised WHO Guidelines for TB Prevention in Resource-Constrained Settings with High TB Incidence & Transmission Adults and adolescents living with HIV, who have an unknown or positive TST and among whom active TB disease has been ruled out should receive at least 36 months of IPT. IPT should be given to such individuals regardless of whether or not they are receiving ART. IPT should also be given irrespective of the degree of immunosuppression, history of previous TB treatment, and pregnancy. (Conditional recommendation, low quality of evidence) WHO, 2015
Meta-Analysis of Three Randomized Controlled Trials Compared outcomes in pts receiving continuous IPT vs. 6-months IPT or equivalent Irrespective of TST = unknown TST status Reduction in mortality for TST-positive (RR 0.50; 95% CI: 0.27-0.91) Significantly more grade 3 or 4 AEs in the continuous IPT group in one study; non-significant increase in the others Adherence 6-mos IPT 83.8% vs. 60.4% for 36-mos in one study Incidence of Active TB Irrespective of TST Continuous IPT 6-month IPT RR (95% CI) 41/1509 (2.7%) 78/1659 (4.7%) 0.62 (0.42-0.89) Positive TST 0.51 (0.30-0.86)
Meta-Analysis of Three Randomized Controlled Trials Den Boon S, et al. AIDS 2016; 30:797-801
Thibela Study: Durability of IPT 9H significantly reduced TB incidence rate only while participants were on the drug Churchyard G, et al. NEJM 2014
Cumulative TB Incidence After 36 Months of IPT Samandari T, et al. AIDS 2015:351-9
THRio Study: Durability of IPT in Medium TB Prevalence Setting 6.52/100 PY ahr 0.17; 95% CI 0.11-0.25 0.53/100 PY Golub JE, et al. Clin Infect Dis 2015; 60:639-45
Obstacles to Uptake of IPT Poor adherence to long duration of IPT Maybe worse with 36 months IPT Insufficient healthcare infrastructure to support DOT or adherence monitoring Risk of toxicity associated with INH Concerns about the inability to effectively rule out subclinical active TB Durability of IPT in high TB prevalence settings
Impact of Antiretroviral Therapy on Risk of TB
Impact of Antiretroviral Therapy on Tuberculosis
Impact of ART on TB Incidence Suthar AB, et al. PLoS Med 2012; 9:e1001270
START: Immediate vs Deferred Therapy for ART-Naive Patients International, randomized trial Study closed by DSMB following interim analysis HIV-positive, ART-naive adults with CD4+ cell count > 500 cells/mm 3 (N = 4685) Immediate ART ART initiated immediately following randomization (n = 2326) Deferred ART Deferred until CD4+ cell count 350 cells/mm 3, AIDS, or event requiring ART (n = 2359) Primary composite endpoint (target = 213) Serious AIDS or death from AIDS Serious non-aids events and death not attributable to AIDS CVD, ESRD, decompensated liver disease, non-aids defining cancers INSIGHT START Study Group. N Engl J Med. 2015;373:795-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
Impact of ART on Tuberculosis INSIGHT START Study Group. N Engl J Med. 2015;373:795-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
Interaction of ART and IPT in Reducing TB Incidence Samandari T, et al. Lancet 2011; 377:1588-98
Cumulative Probability of Death or Severe HIV-Related Illness (%) TEMPRANO: Immediate vs Deferred ART and IPT for African Patients 25 20 15 10 5 30-Mo Probability, % Deferred ART 14.1 Deferred ART + IPT 8.8 Immediate ART 7.4 Immediate ART + IPT 5.7 0 0 6 12 18 24 30 Mos From Randomization TEMPRANO ANRS 12136 Study Group. N Engl J Med. 2015;373:808-822.
Impact of ART and CD4 Count on TB Risk TB Rate Baseline CD4 > 500/mm 3 Early ART/No IPT Early ART/IPT Deferred ART/No IPT Deferred ART/IPT Total TB TB Incidence 8 4 14 8 34 Baseline CD4 < 500/mm 3 TB Incidence 9 7 27 8 51
Can LTBI Treatment Be Shortened in Those on ART?
Short Course Treatment of LTBI in HIV Infection Daily RIF/PZA x 2 mos vs 12-month IPT (Gordin F, et al. JAMA; 2000) N=1,583 HIV-infected, TST+ persons (70% in U.S.) Regimen completion: INH-69% vs. RIF/PZA-80% No differences in TB rates, HIV disease progression or death RIF/PZA Higher discontinuation rates for AEs 2 studies with intermittent RIF/PZA regimens (Zambia, Haiti) overall TB rates higher vs. INH
Rifapentine Long-acting rifamycin-s derivative; inhibits DNA-dependent RNA polymerase T 1/2 ~5x longer than RIF; broader tissue distribution and higher tissue levels than RIF More potent against MTB in vitro (MIC 0.06 vs 0.25 mg/l); greater sterilizing activity in murine models of active TB treatment Treatment-related adverse effects: GI upset/nausea, lightheadedness, dry mouth, diarrhea, headache
Rifapentine-INH Weekly for 3 Months Weekly Twice weekly Martinson NA, et al. NEJM 2011; 365:11-20
TBTC Study 26: Study Design Randomized, open-label study design Treatment arms: Once weekly rifapentine + INH x 12 weeks (DOT) Daily INH x 9 months (self-administered) N=8,053 enrolled Children 2-11 and HIV-infected persons continued enrollment until 12/15/10 33 months of followup from date of enrollment Primary endpoint: Culture confirmed TB in persons > 18 y.o. Culture confirmed or clinical TB in persons < 18 y.o.
TBTC Study 26: TB Event Rates Event rates after 33 months of followup from time of randomization; non-inferiority margin (delta) = 0.75% Sterling TR, et al. NEJM 2011; 365:2155-66
TBTC Study 26: 3HP more effective than 9H? 9H treatment completion 69% 3HP treatment completion 82%
TBTC Study 26: 3HP better tolerated than 9H Adverse Events 3HP N=3986 9H N=3745 P-value Permanent D/C due to AE 4.9% 3.7% 0.009 Hepatotoxicity 0.4% 2.7% < 0.001 Permanent D/C due to Hepatotoxicity Permanent D/C due to Hypersensitivity 0.3% 2.0% < 0.001 2.9% 0.4% < 0.001 Sterling TR, et al. NEJM 2011; 365:2155-66
Study 26: Conclusions Weekly RPT + INH x 3 months was safe and effective in reducing TB rate comparable to daily INH x 9 months in low-medium TB prevalence settings (95% C.I. of difference 0.08%; margin = 0.75%) TB incidence rate (0.19%) lower vs. 9H (0.35%) but did not reach statistical significance Treatment completion rate (82%) was significantly higher vs. 9H (69.5%) Treatment tolerability 3HP better than for 9H
Study 26 Results: HIV-Infected Pts Time to TB by Arm (MITT)
Study 26 Results: HIV-Infected Pts
Shorter Courses of Rifapentine/INH for Treatment of LTBI? Mouse model 10-wk old female BALBc mice Low dose aerosol challenge with virulent strain of MTB (stable lung infection < 10 4 CFU) Quantitative spleen CFU counts in tissue Daily RPT 10 mg/kg/d x 8 wks Daily RPT/INH x 4 wks more effective than RIF/INH and indistinguishable from RIF/PZA x 4 wks Zhang T, et al. Am J Resp Crit Care Med; 2009
ACTG 5279: Ultra-Short Course Daily RPT/INH Prospective, multicenter, randomized trial Study design N=3,000 HIV-infected patients +TST/+IGRA or Reside in TB endemic area where TB rate > 60 cases/100,000 population/year Randomized 1:1 to daily RPT (~10 mg/kg) + INH 300 mg x 4 weeks or daily INH 300 mg x 9 months ART allowed after 4 wks (NRTIs, NNRTIs only) Followed for 3 years after last patient enrolled Results 4 th quarter 2017
TB Preventive Therapy Studies
Proposed Study Schema Single Cycle vs Annual Cycles of HP 6 months INH HIV+, any CD4 cell count, on/starting ART 1 cycle INH/RPT Observation = Randomization N=3378 Annual cycles INH/RPT regardless of CD4 Annual cycles INH/RPT regardless of CD4 Annual cycles INH/RPT regardless of CD4 Month 0 Month 12 Month 24 Month 36
Where do we go from here? One size may not fit all Different uptake and durability depending on TB prevalence settings Poor uptake, limited durability of 6-9 months IPT in medium-high TB prevalence settings Poor uptake of 36P, limited durability in high prevalence settings 3HP not tested in higher TB prevalence settings Effect of ART at higher CD4 on 3HP, 36P efficacy and durability TST, IGRA testing
Questions?