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Economic and modeling evidence for tuberculosis preventive therapy among people living with HIV: A systematic review and meta-analysis

['Aashna Uppal', 'Montréal Chest Institute', 'Montréal', 'Québec', 'Respiratory Epidemiology', 'Clinical Research Unit', 'Centre For Outcomes Research', 'Evaluation', 'Research Institute Of Mcgill University Health Centre', 'Mcgill International Tuberculosis Centre']

Date: 2021-09

Our initial search identified 6,615 titles. One additional article was identified from the reference list of an included article. After titles and abstracts were reviewed, 104 were selected for full text review, of which 61 [12–72] met the study inclusion criteria (Fig 1).

Of the 61 studies included in this review, 51 were classified as high quality and 10 as low quality. The detailed quality assessments are shown in Tables B and C in S1 Text .

Model parameters and data sources for these parameters are summarized in Table D in S1 Text . Although values used for input parameters varied widely, as seen in Table E in S1 Text , there did not appear to be any important differences between parameters that were based on published data, compared to parameters based on assumptions (i.e., no sources or references cited for the values used).

Study characteristics varied widely, and input parameters included in modeling studies were clinically heterogeneous. Study characteristics are summarized in Table 1 , with additional information in Table F in S1 Text . Fifty-four studies (out of 61) used modeling methods to evaluate impact and/or cost-effectiveness of TPT in PLHIV; 28 used modeling methods that excluded TB transmission; and 26 used modeling methods that included transmission. Seven studies that did not use modeling methods were either cost analyses conducted alongside clinical trials (n = 5) or cost-effectiveness evaluations conducted alongside observational studies (n = 2). Thirty-six studies (59%) reported both cost and effectiveness or utility outcomes, 25 (41%) reported effectiveness or utility outcomes only, and 5 (8%) reported cost outcomes only. Forty-one (67%) studies were set in LMICs, of which 33 (80%) studies were set in the African Region. Forty-five (74%) studies evaluated 6 to 12 months of daily INH; only 9 (15%) studies considered rifamycin-based regimens for TPT. Thirty-six (59%) studies explored the use of TST or IGRA to guide the decision to recommend TPT (i.e., those with a positive TST or IGRA were provided TPT).

Projected outcomes and study conclusions

In all studies that reported effectiveness or utility outcomes, compared to no TPT, the provision of TPT for PLHIV was more effective at reducing active TB incidence, TB-related mortality, and DALYs and was more effective at increasing QALYs and life expectancy (Tables G and H in S1 Text).

There were 68 unique strategies within studies that reported a relative reduction in active TB incidence comparing PLHIV given TPT to PLHIV not given TPT, which also specified a TPT regimen. Modeling strategies among these studies were heterogeneous, as were model parameters. Twenty-six studies considered TB transmission, and 42 did not consider TB transmission. The median TPT efficacy in preventing active TB ranged from 0.11 to 1 and percent completion of TPT ranged from 7% to 100%, for example. As seen in Fig 2, the relative reduction in active TB incidence with TPT compared to no TPT ranged from nearly 0% to nearly 100%. There was no apparent effect on reduction in active TB incidence between modeling studies that considered versus did not consider TB transmission; the median percent reduction in active TB incidence was 28% (interquartile range [IQR] 19% to 51%) among studies modeling without TB transmission and 28% (IQR 11% to 70%) among studies modeling with TB transmission. On the other hand, the median percent reduction in active TB incidence was 28% (IQR 17% to 50%) in LMICs, whereas it was 48% (IQR 20% to 63%) in HICs. The latter association is further explored in regression analyses.

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TIFF original image Download: Fig 2. Percent reduction in active TB incidence in studies comparing TPT versus no TPT, by TPT regimen and country-level income. INH, isoniazid; RIF, rifampin; RPT, rifapentine; TB, tuberculosis; TPT, tuberculosis preventive therapy. Each data point represents a study arm. Modeling methods are distinguished in this figure; filled black squares (■) represent decision analysis models, while filled gray circles (●) represent transmission models. https://doi.org/10.1371/journal.pmed.1003712.g002

Of the 38 studies that reported cost outcomes, 9 obtained cost parameters exclusively from secondary data sources, while 10 employed empiric costing methods, gathering cost parameters exclusively from primary data sources (Table 1). Of those that undertook empiric costing or a combination of simple and empiric costing, 15 studies included costs associated with TPT implementation. Most of these 38 studies were modeling studies that excluded transmission (n = 30), while a minority were transmission modeling studies (n = 4) or analyses conducted alongside clinical trials or observational studies (n = 4). Within these 38 studies, parameters differed widely; TPT efficacy in averting active TB ranged from 0.11 to 1, time horizon ranged from 1 to 100 years, and LTBI prevalence ranged from 0.03 to 1. The per-person costs of TPT did not vary greatly by regimen, regardless of country-level income, as seen in Fig 3. The strategies included in Fig 3 (n = 63) compared TPT to no TPT and included the downstream health systems costs related to active TB care. The median per-person cost was $299 (IQR $73 to $756) among these strategies. Six other strategies also reported per-person costs for TPT, but excluded downstream health systems costs related to active TB care. The median per-person cost was $148 (IQR $117 to $579) among these 6 strategies. The use of ART also contributed to the magnitude of per-person costs of TPT; the median cost among studies that considered the cost of ART was $592 (IQR $152 to $756), whereas the median cost among studies that did not consider the cost of ART was $195 (IQR $65 to $365).

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TIFF original image Download: Fig 3. Per-person cost of TPT versus no TPT, by TPT regimen and country-level income. ART, antiretroviral therapy; INH, isoniazid; RIF, rifampin; RPT, rifapentine; TB, tuberculosis; TPT, tuberculosis preventive therapy. Each data point represents a study arm or “strategy.” Outliers are analyzed in further detail in the Outliers section of S1 Text. Costs displayed in this figure include program costs related to TPT delivery (drug costs, personnel costs, and material costs) as well as costs related to TB care for those who develop active TB (drug costs, hospitalization costs, and personnel costs). Importantly, these come from studies that compared the use of TPT to no TPT and do not include studies that comparing directed TPT to TPT for all. The use of ART is distinguished in this figure; filled black squares (■) represent strategies that included the cost of ART, while filled gray circles (●) represent strategies that did not include the cost of ART. https://doi.org/10.1371/journal.pmed.1003712.g003

Of the 47 unique strategies within studies that reported incremental cost per active TB case averted, 35 were set in LMICs, while 12 were set in HICs. Values of model parameters varied widely; the median LTBI prevalence was 0.26 (range 0.02 to 0.64), the median time horizon was 3 years (range 1 to 20 years), and the median TPT efficacy was 0.49 (range 0.11 to 0.90). Despite this heterogeneity in model parameter values, in all studies, authors concluded TPT was predicted to be cost-effective compared to no TPT, even with diverse willingness-to-pay thresholds specific to each study setting. Four studies found TPT was predicted to be cost saving compared to no TPT [15,28,54,68], and 2 studies concluded TPT was estimated to be “highly” cost-effective [20,30]. Three studies set in HICs with low TB incidence concluded that using TST or IGRA to guide the decision to provide TPT was potentially more cost-effective than providing TPT to all PLHIV [44,46,69]. On the other hand, 2 studies set in LMICs concluded that providing TPT to all pregnant women living with HIV would be potentially more cost-effective than using TST or IGRA to guide TPT decisions in this population [41,43].

As seen in Fig 4, all studies found that providing TPT to PLHIV was predicted to be more effective at averting active TB cases than not providing TPT (Fig 4); a minority (n = 4) of these studies found that TPT was potentially both cost saving and more effective than no TPT. Comprehensive outcomes and conclusions from each study are reported in Tables I and J in S1 Text.

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