TB prevention studies in PLHIV: recent updates and what can they tell us for the future? Richard E. Chaisson, MD Center for AIDS Research Center for TB Research Johns Hopkins University TB/HIV Working Group Meeting Washington, DC February 11-12, 2014
Preventive Interventions in TB/HIV Prevent Infection Treat HIV Chemoprophylaxis
Population-level interventions to control TB/HIV The Consortium to Respond Effectively to the AIDS-TB Epidemic (CREATE) Study Intervention(s) Design (N) Mass TB preventive therapy for S.A. gold miners Enhanced TB case finding, contact evaluations in Zambia and S.A. Preventive therapy and ARVs for HIV patients in Rio de Janeiro Cluster randomized trial (~80,000) Community randomized trial (~1 million) Phased implementation trial (18,000)
THRio Study Design and Timeline Cluster-Randomized, Stepped Wedge Trial Intervention and Follow-up Period (for all clinics) 48 60 Sep 05 Jan 08 Adapted from Moulton LH, Golub JE, Durovni B et al. Clinical Trials 2007;4:190 Aug 09 4
Proportion with no PPD 0.0 0.2 0.4 0.6 0.8 1.0 Time to TST and Time to INH Before and After THRio Intervention Proportion with no IPT 0.0 0.2 0.4 0.6 0.8 1.0 Time to TST Time to PPD Time to Time IPT to IPT for TST+ Pre-intervention Post-intervention Pre-intervention Post-intervention 19/100 PYs 36/100 PYs 0 50 100 150 200 Weeks 59/100 PYs 0 50 100 150 Weeks 144/100 PYs Durovni et al., AIDS 2010, 24 (suppl 5):S49 S56
Rates and risks of TB after intervention in the THRio Study Intent To Treat Perprotocol (Stayers) Outcome Cases Crude HR (95% CI) p-value TB 475 0.87 (0.69-1.10) 0.24 TB or Death 1313 0.76 (0.66-0.87) <0.001 TB 399 0.43 (0.31-0.58) Adjusted HR (95% CI) 0.73 (0.54-0.99) 0.69 (0.57-0.83) <0.001 0.42 (0.31-0.58) p-value 0.04 <0.001 <0.001 TB or Death 1055 0.50 (0.41-0.60) <0.001 0.50 (0.41-0.60) <0.001 Stayers per-protocol - Among those remaining in clinic contact (Patients censored after one year without a clinic contact) Durovni et al., Lancet Infect Dis. 2013;10:852-8
Durability of INH Preventive Therapy Effectiveness in THRio All Patients Golub et al, CROI 2013
Durability of INH Preventive Therapy Effectiveness in THRio By Treatment Completion Non-completers Completers Golub et al, CROI 2013
Thibela TB N=78,000, 8 intervention clusters, 7 control IPT arm: Community education and mobilization Intervention offered to entire workforce Screening for active TB: symptoms and chest X-ray if symptomatic / abnormal CXR, one sputum sent for microscopy, culture, DST People with suspected TB referred for treatment If eligible, 9 months of IPT 300mg daily, self-administered, monthly follow-up Churchyard et al. N Engl J Med 2014;370:301-10.
Thibela TB: TB Incidence Among employees in the primary outcome measurement period: TB Person years Rate/100 py Intervention 887 29,352 3.02 Control 856 29,014 2.95 Incidence rate ratio Unadjusted 1.00 (95% CI 0.75-1.34) Adjusted* 0.96 (95% CI 0.76-1.21) *Adjusted for gender, age, place of work (at individual level) and silicosis, ART use, TB CNR Churchyard et al. N Engl J Med 2014;370:301-10.
Thibela TB: TB Prevalence Among a sample of employees at study end: TB (n) Total (N) Prevalence (%) Intervention 166 7,049 2.35 Control 119 5,557 2.14 Prevalence rate ratio Unadjusted 1.05 (95% CI 0.60-1.82) Adjusted* 0.98 (95% CI 0.65-1.48) *Adjusted for gender, age, place of work (individual level); silicosis, ART use, TB CNR (cluster level) Churchyard et al. N Engl J Med 2014;370:301-10.
TB incidence per 100 pyrs Thibela TB: IPT effective at individual level, but effect short-lived 3.5 3 2.5 2 1.5 1 0.5 0 0-9 m 9-18m >18m 58% reduction in TB incidence during 9m of intervention TB inc rate: control IPT Control arm 0-9m 9-18m >18m 2.91 1.10 2.71 2.34 2.70 2.42 adjusted RR 0.42 0.93 0.95 Churchyard et al. N Engl J Med 2014;370:301-10.
TST-positive, 6 months IPT TST- negative, 6 months IPT TST-negative, 36 months IPT TST-positive, 36 months IPT Days after enrollment Lancet. 2011;377:1588-1598.
Number of cases/100,000/year (true incidence) Thibela TB: what will it take to control TB control in gold mines? 4000 3000 2000 1000 Reduce treatment delay Better diagnostics Maximise ART coverage Better preventive therapy 0 Churchyard, White, et al. SA TB Conf 2012
Short-course TB Preventive Regimens vs Lifelong IPT in HIV+ Patients Outcome Rifapentine/INH Weekly x 12 wks (n = 328) RIF/INH Twice Weekly x 12 wks (n = 329) INH daily for up to 6 yrs (n = 164) INH daily for 6 months (n = 327) Median f/u 4.0 yrs 4.1 yrs 3.9 yrs 3.9 yrs TB or death (per 100 PY) 3.1 2.9 2.7 3.6 TB or death Rate ratio 0.87 (0.54-1.39) 0.80 (0.50-1.29) 0.75 (0.38-1.38) 1 (ref) (95% CI) Martinson et al., NEJM 2011;365:11-20
Effectiveness of Life-long INH in TST+/HIV+ Patients Intent-to-treat vs. as-treated Martinson et al., NEJM 2011;365:11-20
Efficacy of IPT in Patients on ART Pragmatic RCT in Cape Town (Ubuntu clinic in Khayelitsha) Eligibility = HIV+ starting ART or on established ART, >18 years, no TB 1,329 participants, 3227 person-years Median CD4 = 216 (IQR 152-360) 662 on placebo and 667 on IPT for 12 months Rangaka et al., Lancet, in press.
Rangaka et al., Lancet, in press.
Rangaka et al., Lancet, in press. Effect of IPT on TB by IGRA and TST Status Placebo Isoniazid Effect IGRA Rate/100 PY Rate/100 PY HR a Negative 3.3 1.3 0.43* (0.20-0.96) Positive 3.9 3.0 0.55 (0.26-1.24) TST Negative 4.1 1.7 0.43* (0.21-0.86) Positive 2.8 2.6 0.86 (0.37-2.0) *P<0.05
The impact of preventive therapy on control of TB in high-burden areas
Implications IPT works for HIV+ patients in high- and lowincidence areas IPT works in advanced HIV disease and in TST negative patients In high-incidence areas, benefit may not be durable and prolonged PT may be needed In medium- and low- incidence areas, shortcourse PT appears to be effective Lack of long-term efficacy could be due to reinfection or failure to sterilize latent infection Combination preventive interventions for TB and HIV are essential