Background
Methods
TPT simulation model
Parameter estimation
Cohort composition
Parameter type | Definition | Data sources and approach to estimation | Table in Additional file 1 with estimates, uncertainty, and references |
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Prevalence of “latent progressor” state among each cohort considered for TPT | Latent infections that will progress to active (symptomatic) TB disease at some time in the future | Lifetime cumulative incidence extrapolated from observed 12-month incidence (PWH cohort) or baseline prevalence (household contacts) using published cohort studies and meta-analyses | Table S1 |
Prevalence of “subclinical progressor” state among each cohort considered for TPT | TB disease that is undetectable by a symptom screen but is microbiologically active and will eventually progress to active disease if untreated | Primary clinical data (Table 2): Symptom-negative individuals who progressed to active TB within 3 months (PWH) or who were diagnosed with TB during extensive baseline evaluation (household contacts, with adjustment for expected spontaneous resolution). | Table S1 |
Efficacy of TPT for latent progressors, by regimen | Proportion of latent progressions prevented, if initially susceptible to the TPT regimen and completes enough TPT to be at risk for acquired resistance | Network meta-analysis of clinical trial data, adjusted for reinfection, nonadherence, and baseline drug resistance. 6H efficacy parametrized relative to 4R and assumed equal or less than 4R. | Table S2 |
Reduction in TPT efficacy when used during subclinical TB | Proportion of TPT-preventable latent progressions that cannot be cured by TPT at the subclinical progressor stage | Bounded by the efficacy of TPT for latent TB and by the efficacy of monotherapy for symptomatic active TB. | Table S2 |
Risk of acquiring resistance to the TPT drug, if latent TB progresses despite TPT | Applies to those whose TPT is unsuccessful and whose initial infections were not drug-resistant. | Incidence of drug-resistant TB after TPT in clinical trials, adjusted for expected incidence from pre-existing drug resistance. Risk for isoniazid sets an upper bound on risk for rifampicin. | Table S3 |
Risk of acquiring resistance to the TPT drug, if subclinical TB progresses despite TPT | As above | Treatment trials with a single effective drug. Large uncertainty is reflected in wide parameter distributions. | Table S3 |
Outcomes after active TB treatment | Risk of failure/relapse, with or without acquired isoniazid or rifampicin resistance, as a function of initial susceptibilities. | Previous reviews of clinical trial and research cohort outcomes. Weighted based on the regimens expected to be used in present-day programmatic settings, including the use of first-line regimens when drug resistance goes undetected. | Table S4 |
Prevalence and overlap of INH and RIF resistance | Same for subclinical cases and latent progressors | Drug resistance survey data; lower in contacts of DS-TB patients than among all TB infections | Table S4 |
Baseline drug resistance | Prevalence and overlap of isoniazid and rifampicin resistance among TB infections in a modeled cohort. | National or regional drug resistance survey data, adjusted downward for household contacts of known DS-TB patients | Table S5 |
People newly diagnosed with HIV, Kwa-Zulu Natal, South Africa | Household contacts, Pakistan | ||||||
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CD4 < 100 | CD4 100–200 | CD4 200–350 | CD4 > 350 | Age < 5 years | Age 5–14 years | Age ≥ 15 years | |
Total evaluated | 379 | 442 | 785 | 1392 | 2194 | 4261 | 6648 |
Symptomatic TB at baseline, N (%) | 93 (24.5%) | 56 (12.7%) | 42 (5.4%) | 43 (3.1%) | 42 (1.9%) | 86 (2%) | 28 (0.4%) |
Subclinical TB diagnosed at baseline, N (%) | 19 (0.9%) | 58 (1.4%) | 29 (0.4%) | ||||
Subclinical TB progressed to active within 3 months | 16 (4.2%) | 17 (3.8%) | 28 (3.6%) | 44 (3.2%) | |||
Followed to 6 months | 359 | 406 | 740 | 1312 | NA | NA | NA |
TB diagnoses, 3 to 6 months, N (% | 2 (0.6%) | 4 (1%) | 2 (0.3%) | 0 (0%) | |||
Followed to 12 months | 314 | 348 | 625 | 1096 | NA | NA | NA |
TB diagnoses, 6 to 12 months, N (% | 7 (2.2%) | 7 (2%) | 5 (0.8%) | 7 (0.6%) | |||
Estimated lifetime incidence (95%CI) of progression of latent infections present at enrollmenta | 4.7% (2.7–6.8%) | 4.9% (2.9–7.1%) | 3.0% (1.7–4.2%) | 2.5% (2.5–3.4%) | 0.6% (0.3–1.0%) | 3.7% (2.3–5.3%) | 1.2% (0.8–1.8%) |
Estimated subclinical prevalent cases per future latent progression | 1.4 | 0.4 | 0.4 | ||||
Estimated subclinical progressors per latent progressor (95%CI)b | 0.9 (0.6–1.4) | 0.8 (1.5–1.2) | 1.2 (0.8–1.9) | 1.2 (0.9–1.9) | 0.7 (0.4–1.2) | 0.2 (0.1–0.3) | 0.2 (0.1–0.3) |
TPT outcome parameters
Simulation of outcomes
Results
Outcomes without TPT intervention
Impact of TPT with symptom-only TB screening
4R, symptom screening only | 4R, Subclinical TB screening, same access | 4R, Subclinical TB screening, 20% reduced access | 6H, symptom screening only | 6H, Subclinical TB screening, same access | 6H, Subclinical TB screening, 20% reduced access | |
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PWH cohort | ||||||
Expected cases of active TB without TPT | 71 | 71 | 71 | 71 | 71 | 71 |
Expected cases of active TB with TPT # | 25 | 16 | 27 | 33 | 20 | 31 |
Net change in total active TB cases (versus no TPT) a | −45 | −55 | −44 | −37 | −51 | −41 |
Net change in INH monoresistant cases (versus no TPT) | −3 | −2.9 | − 2.3 | 6.2 | −0.48 | − 0.38 |
Net change in RIF monoresistant cases (versus no TPT) | 3 | 0.3 | 0.24 | −0.23 | −0.11 | − 0.09 |
Net change in MDR cases (versus no TPT) | 0.63 | −0.56 | −0.45 | 0.18 | −0.59 | − 0.47 |
Net change in total DR cases (versus no TPT) | −0.85 | −1.5 | − 1.2 | 1.1 | − 0.69 | − 0.55 |
Symptomatic TB cases averted per RR/MDR added (vs no TPT) | 12 | b | b | b | b | b |
INH monoresistance averted per RR/MDR added (vs no TPT) | 0.78 | b | b | b | b | b |
Symptomatic TB cases averted per RR/MDR added (vs 6H) | 2 | 7.2 | 7.2 | NA | NA | NA |
INH monoresistance averted per RR/MDR added (vs 6H) | 2.3 | 4 | 4 | NA | NA | NA |
Household contact cohort | ||||||
Expected cases of active TB without TPT | 25 | 25 | 25 | 25 | 25 | 25 |
Expected cases of active TB with TPT # | 7.8 | 6.8 | 10 | 12 | 10 | 13 |
Net change in total active TB cases (versus no TPT) a | −17 | −18 | −15 | −13 | −15 | −12 |
Net change in INH monoresistant cases (versus no TPT) | −1.6 | − 1.6 | −1.3 | 0.84 | −0.02 | −0.02 |
Net change in RIF monoresistant cases (versus no TPT) | 0.39 | 0.09 | 0.07 | −0.06 | −0.05 | − 0.04 |
Net change in MDR cases (versus no TPT) | 0.02 | −0.1 | −0.08 | 0 | −0.06 | − 0.05 |
Net change in total DR cases (versus no TPT) | −0.56 | − 0.56 | −0.44 | 0.11 | −0.09 | − 0.07 |
Symptomatic TB cases averted per RR/MDR added (vs no TPT) | 37 | b | b | b | b | b |
INH monoresistance averted per RR/MDR added (vs no TPT) | 3.5 | b | b | b | b | b |
Symptomatic TB cases averted per RR/MDR added (vs 6H) | 7.2 | 24 | 24 | NA | NA | NA |
INH monoresistance averted per RR/MDR added (vs 6H) | 5 | 13 | 13 | NA | NA | NA |