Impact and cost-effectiveness of short-course tuberculosis preventive treatment for household contacts and people with HIV in 29 high-incidence countries: a modelling analysis

Abstract

Background: Guidelines and implementation of tuberculosis preventive treatment (TPT) vary by age and HIV status. Specifically, TPT is strongly recommended for people living with HIV/AIDS (PLWHA) and household contacts younger than 5 years but only conditionally recommended for older contacts. Cost remains a major barrier to implementation. The aim of this study was to evaluate the cost-effectiveness of TPT for household contacts and PLWHA.

Methods: We developed a state-transition model to simulate short-course TPT for household contacts and PLWHA in 29 high-incidence countries based on data from previous studies and public databases. Our primary outcome was the incremental cost-effectiveness ratio, expressed as incremental discounted costs (2020 US$, including contact investigation costs) per incremental discounted disability-adjusted life year (DALY) averted, compared with a scenario without any TPT or contact investigation. We propagated uncertainty in all model parameters using probabilistic sensitivity analysis and also evaluated the sensitivity of results to the screening algorithm used to rule out active disease, the choice of TPT regimen, the modelling time horizon, assumptions about TPT coverage, antiretroviral therapy discontinuation, and secondary transmission.

Findings: Between 2023 and 2035, scaling up TPT prevented 0·9 (95% uncertainty interval 0·4-1·6) people from developing tuberculosis and 0·13 (0·05-0·27) tuberculosis deaths per 100 PLWHA, at an incremental cost of $15 (9-21) per PLWHA. For household contacts, TPT (with contact investigation) averted 1·1 (0·5-2·0) cases and 0·7 (0·4-1·0) deaths per 100 contacts, at a cost of $21 (17-25) per contact. Cost-effectiveness was most favourable for household contacts younger than 5 years ($22 per DALY averted) and contacts aged 5-14 years ($104 per DALY averted) but also fell within conservative cost-effectiveness thresholds in many countries for PLWHA ($722 per DALY averted) and adult contacts ($309 per DALY averted). Costs per DALY averted tended to be lower when compared with a scenario with contact investigation but no TPT. The cost-effectiveness of TPT was not substantially altered in sensitivity analyses, except that TPT was more favourable in analysis that considered a longer time horizon or included secondary transmission benefits.

Interpretation: In many high-incidence countries, short-course TPT is likely to be cost-effective for PLWHA and household contacts of all ages, regardless of whether contact investigation is already in place. Failing to implement tuberculosis contact investigation and TPT will incur a large burden of avertable illness and mortality in the next decade.

Funding: Unitaid.

Figure 1

Model diagrams In A–D white boxes indicate populations and sub-populations, and coloured boxes indicate processes of contact investigation and TPT. (A) contact investigation for children younger than 5 years is assumed to screen for tuberculosis based on symptom screening only. Those with positive symptom screening are tested using chest x-ray, and those with chest x-rays suggestive of tuberculosis are initiated on tuberculosis treatment (including both true and false positives). All those presumed to not have tuberculosis disease (negative symptom screening or normal chest x-ray; including both true and false negatives) are eligible to initiate TPT. (B) Contacts aged 5 years and older (including contacts aged 5–14 years and contacts aged 15 years and older) are screened using both symptom screening and chest x-ray. Those with positive symptom screening or abnormal chest x-ray, or both, are tested for tuberculosis disease using Xpert MTB/RIF. Contacts who are Xpert positive (including both true and false positives) are initiated on tuberculosis treatment, and contacts who are Xpert negative and those with both negative symptom screening and normal chest x-ray are eligible to initiate TPT (including both true and false negatives). For household contacts of all ages with tuberculosis infection who are improperly treated for tuberculosis disease (false positives), treatment is assumed to cure their infections (see panel E). Household contacts of all ages with tuberculosis disease who are improperly given TPT or not given any treatment (false negatives) continue to have active disease until detected through the health system (based on background notifications; see panel E). (C) PLWHA taking antiretroviral therapy are assumed to be screened and tested for tuberculosis on a regular basis, such that active disease is detected promptly and treatment is subsequently initiated (see panel E). PLWHA for whom tuberculosis is not detected are eligible to initiate TPT during a routine health system visit. (D) Once TPT is initiated, both household contacts and PLWHA may complete the full course (full efficacy achieved), complete a partial course (50% efficacy achieved), or discontinue TPT due to an adverse event (no efficacy achieved). Those initiating TPT with tuberculosis infection are cured of their infections based on efficacy; those initiating TPT without tuberculosis infection are unaffected (see panel E). After following the decision trees in panels A–D, cohorts enter a Markov model that tracks their tuberculosis status on an annual basis (panel E). (E) Circles indicate states and arrows indicate transitions between states. Among PLWHA, antiretroviral therapy status is also tracked in the Markov model (panel E). Additional details for the Markov model are in the appendix (pp 4–6). LTBI=latent tuberculosis infection. PLWHA=people living with HIV/AIDS. TPT=tuberculosis preventive treatment.

Figure 2

Mean per-person costs of scaling up short-course TPT for PLWHA and household contacts across 29 countries (A–D) Mean tuberculosis-related costs per household contact (of each age group) and per eligible PLWHA in 29 countries of tuberculosis treatment in a population not initiating TPT, in a population for whom 3HP is scaled up through 2035, and the mean per-person cost differences between the two scenarios (incremental cost). Costs include tuberculosis treatment, contact investigations, 3HP, and adverse events. (E) The same costs as panel D, but includes antiretroviral therapy costs for PLWHA. Text labels indicate mean costs, with 95% UI (2·5th and 97·5th percentiles) from the 50 000 probabilistic sensitivity analysis samples in brackets. Contact investigation and ruling out active tuberculosis comprised 39% of incremental costs among children younger than 5 years and 65–70% of incremental costs among older contacts. 3HP drugs and delivery comprised 18% (contacts younger than 5 years), 26% (contacts aged 5–14 years), and 35% (contacts aged 15 years and older) of incremental costs. Additional tuberculosis treatment accounted for 42% (95% UI 12–66) of total incremental costs to contacts younger than 5 years, and tuberculosis treatment savings were expected among contacts aged 15 years and older. 95% UI=95% uncertainty intervals. 3HP=12 weeks of isoniazid and rifapentine. PLWHA=people living with HIV/AIDS. TPT=tuberculosis preventive treatment.

Figure 3

Mean per-person health impact of scaling up 3HP for PLWHA and household contacts in 29 countries (A) Mean active tuberculosis cases per 100 eligible people (ie, per household contact of each of three age groups, displayed in years, or per PLWHA) across 29 countries, in populations not initiating TPT, populations for whom TPT is scaled up through 2035, and the incremental cases averted between the two scenarios (cases averted). (B) The same cumulative outcomes and differences by scenario and population as in A, but for tuberculosis deaths rather than cases. Note the difference in scale on the y axis for the two outcomes. 3HP=12 weeks of isoniazid and rifapentine. PLWHA=people living with HIV/AIDS. TPT=tuberculosis preventive treatment.

Figure 4

Cost-effectiveness of 3HP for household contacts and PLWHA in 29 countries Each marker represents a country-specific estimate of discounted incremental DALYs averted per person (ie, per household contact or PLWHA) from implementing 3HP (x axis) and corresponding discounted incremental costs (y axis), compared with a scenario of no TPT for household contacts younger than 5 years (A), household contacts aged 5–14 years (B), household contacts aged 15 years and older (C), and PLWHA (D). Both x and y axes are on a log scale. Countries are labelled by their 3-digit ISO codes (positions of country code labels have been jittered to avoid overlaps), and population-weighted means across the 29 countries are designated via a white star. Shaded areas indicate incremental cost-effectiveness ratios. For example, in B, the plot indicates that the incremental cost-effectiveness ratio of 3HP for contacts aged 5–14 years in ZAF is between $100 and $500 per DALY averted, and in D, the plot indicates that the incremental cost-effectiveness ratio of tuberculosis preventive treatment for PLWHA in ZAF is between $500 and $1000 per DALY averted. Cambodia, Eswatini, Mongolia, and Namibia are omitted from panel D because scaling up 3HP for PLWHA in these countries was estimated to be cost saving; there were no countries for which the intervention was cost saving in the other analyses presented in A–C. Values and cost-effectiveness thresholds for each country are in the appendix (pp 56–58). 3HP=12 weeks of isoniazid and rifapentine. DALY=disability-adjusted life year. PLWHA=people living with HIV/AIDS. BDI=Burundi. BGD=Bangladesh. BRA=Brazil. COD=DR Congo. ETH=Ethiopia. GHA=Ghana. HTI=Haiti. IDN=Indonesia. IND=India. KEN=Kenya. KHM=Cambodia. LBR=Liberia. LSO=Lesotho. MNG=Mongolia. MOZ=Mozambique. MWI=Malawi. NAM=Namibia. PAK=Pakistan. RWA=Rwanda. SOM=Somalia. SWZ=Eswatini. THA=Thailand. TJK=Tajikistan. TLS=Timor-Leste. TZA=Tanzania. UGA=Uganda. ZAF=South Africa. ZMB=Zambia. ZWE=Zimbabwe.