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The latent tuberculosis cascade-of-care among people living with HIV: A systematic review and meta-analysis

['Mayara Lisboa Bastos', 'Respiratory Epidemiology', 'Clinical Research Unit', 'Research Institute Of The Mcgill University Health Centre', 'Montreal', 'Social Medicine Institute', 'State University Of Rio De Janeiro', 'Rio De Janeiro', 'Department Of Medicine', 'Mcgill University']

Date: 2021-09

Abstract Background Tuberculosis preventive therapy (TPT) reduces TB-related morbidity and mortality in people living with HIV (PLHIV). Cascade-of-care analyses help identify gaps and barriers in care and develop targeted solutions. A previous latent tuberculosis infection (LTBI) cascade-of-care analysis showed only 18% of persons in at-risk populations complete TPT, but a similar analysis for TPT among PLHIV has not been completed. We conducted a meta-analysis to provide this evidence. Methods and findings We first screened potential articles from a LTBI cascade-of-care systematic review published in 2016. From this study, we included cohorts that reported a minimum of 25 PLHIV. To identify new cohorts, we used a similar search strategy restricted to PLHIV. The search was conducted in Medline, Embase, Health Star, and LILACS, from January 2014 to February 2021. Two authors independently screened titles and full text and assessed risk of bias using the Newcastle–Ottawa Scale for cohorts and Cochrane Risk of Bias for cluster randomized trials. We meta-analyzed the proportion of PLHIV completing each step of the LTBI cascade-of-care and estimated the cumulative proportion retained. These results were stratified based on cascades-of-care that used or did not use LTBI testing to determine eligibility for TPT. We also performed a narrative synthesis of enablers and barriers of the cascade-of-care identified at different steps of the cascade. A total of 71 cohorts were included, and 70 were meta-analyzed, comprising 94,011 PLHIV. Among the PLHIV included, 35.3% (33,139/94,011) were from the Americas and 29.2% (27,460/94,011) from Africa. Overall, 49.9% (46,903/94,011) from low- and middle-income countries, median age was 38.0 [interquartile range (IQR) 34.0;43.6], and 65.9% (46,328/70,297) were men, 43.6% (29,629/67,947) were treated with antiretroviral therapy (ART), and the median CD4 count was 390 cell/mm3 (IQR 312;458). Among the cohorts that did not use LTBI tests, the cumulative proportion of PLHIV starting and completing TPT were 40.9% (95% CI: 39.3% to 42.7%) and 33.2% (95% CI: 31.6% to 34.9%). Among cohorts that used LTBI tests, the cumulative proportions of PLHIV starting and completing TPT were 60.4% (95% CI: 58.1% to 62.6%) and 41.9% (95% CI:39.6% to 44.2%), respectively. Completion of TPT was not significantly different in high- compared to low- and middle-income countries. Regardless of LTBI test use, substantial losses in the cascade-of-care occurred before treatment initiation. The integration of HIV and TB care was considered an enabler of the cascade-of-care in multiple cohorts. Key limitations of this systematic review are the observational nature of the included studies, potential selection bias in the population selection, only 14 cohorts reported all steps of the cascade-of-care, and barriers/facilitators were not systematically reported in all cohorts. Conclusions Although substantial losses were seen in multiple stages of the cascade-of-care, the cumulative proportion of PLHIV completing TPT was higher than previously reported among other at-risk populations. The use of LTBI testing in PLHIV in low- and middle-income countries was associated with higher proportion of the cohorts initiating TPT and with similar rates of completion of TPT.

Author summary Why was this study done? Tuberculosis (TB) remains as one of the main causes of deaths among people living with HIV (PLHIV).

Tuberculosis preventive therapy (TPT) reduces TB-related morbidity and mortality PLHIV.

Previous meta-analysis has shown that many losses occurred in the TPT cascade-of-care. However, a similar analysis has not been conducted in PLHIV. What did the researchers do and find? We conducted a systematic review and meta-analysis evaluating the TPT cascade-of-care among PLHIV. We constructed 2 cascade-of-care frameworks: (1) studies that did not use LTBI tests to determinate TPT eligibility; and (2) studies that used LTBI tests to determinate TPT eligibility.

We performed stratified analyses by income setting (high-income versus low- and middle-income countries) and type of clinics where patients were followed (HIV clinics versus other clinics). We also performed meta-regression using adjusting these 2 variables.

Among the cohorts that did not use LTBI tests, the cumulative proportion of PLHIV completing TPT was 33.2% and 41.9% among cohorts that used LTBI tests. This was not statistically significant when we performed meta-regression by income and type of clinics. What do these findings mean? The cumulative proportion of PLHIV completing TPT was higher than was previously reported among other at-risk populations.

Recommendation and initiation of TPT was higher, and completion similar among cohorts that used LTBI tests, compared to cohorts offered TPT without LTBI testing.

The use of LTBI test was not an important barrier for TPT.

Substation losses remained in the TPT cascade-of-care, and continuous efforts are necessary to improve TPT care among PLHIV.

Citation: Bastos ML, Melnychuk L, Campbell JR, Oxlade O, Menzies D (2021) The latent tuberculosis cascade-of-care among people living with HIV: A systematic review and meta-analysis. PLoS Med 18(9): e1003703. https://doi.org/10.1371/journal.pmed.1003703 Academic Editor: Amitabh Bipin Suthar, PLOS Medicine Editorial Board, UNITED STATES Received: December 11, 2020; Accepted: June 20, 2021; Published: September 7, 2021 Copyright: © 2021 Bastos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the manuscript and its Supporting Information files. Funding: This work was funded by the Bill & Melinda Gates Foundation (Grant Number INV-003634). The initial study questions for the papers included in the PLOS Collection were drafted together with input from staff of the Bill & Melinda Gates Foundation, but they had no further role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: ART, antiretroviral therapy; IGRA, interferon gamma release assay; IQR, interquartile range; LTBI, latent tuberculosis infection; PEPFAR, President’s Emergency Plan for AIDS Relief; PLHIV, people living with HIV; RCT, randomized clinical trial; TB, tuberculosis; TPT, tuberculosis preventive therapy; TST, tuberculin skin test

Introduction Tuberculosis (TB) remains a significant public health problem, particularly among people living with HIV (PLHIV). In 2019 alone, nearly 25% of PLHIV with TB disease died [1]. Tuberculosis preventive therapy (TPT) works synergistically with, and independently of, antiretroviral therapy (ART) to reduce TB incidence among PLHIV [2–4]. To scale up TPT in PLHIV, WHO has simplified its algorithm for TPT initiation by not requiring latent tuberculosis infection (LTBI) tests prior to initiation [4]. Either a tuberculin skin test (TST) or interferon gamma release assay (IGRA) can identify people who have LTBI, but these tests have reduced sensitivity among PLHIV due to impaired T-cell immunity. While PLHIV with a positive LTBI test are at substantially increased risk for active TB compared to PLHIV with a negative test, those with a negative test still experience TB disease at rates about 5 times higher than the general population [5]. For this reason, WHO recommendations permit TPT without the requirement of LTBI testing. In 2019, 50% (3.5 million) of PLHIV newly enrolled in care initiated TPT compared to 1.5 million initiating TPT in 2018 [1]. However, these figures fail to capture the complete picture. Half of individuals eligible for TPT never initiated it, and it is uncertain how many of those initiated TPT completed it [1]. Thus, important barriers other than LTBI testing remain to be elucidated. Cascade-of-care frameworks are increasingly used to identify gaps and barriers in care in order to develop targeted solutions [6–9]. These frameworks describe population-level engagement in the sequential steps of healthcare delivery systems in which patients must pass through multiple interventions to reach a desired outcome. Such cascades have been invaluable in highlighting gaps in HIV diagnosis and treatment implementation [10] and more recently have been used to broadly assess TPT uptake [11]. To help identify care gaps and potential targeted solutions, we conducted a systematic review and meta-analysis evaluating the LTBI cascade-of-care for TPT among PLHIV.

Discussion In this meta-analysis exclusively in PLHIV, we found that cumulative TPT completion was similar in studies that used or did not use LTBI tests and also similar in studies from high- or low- and middle-income income settings, regardless of use of LTBI tests. Despite the losses in multiples stages, overall TPT completion was better than overall completion observed in an earlier review that included multiple at-risk populations [11]. Health system facilitators included training of healthcare workers for TPT, and integration of TB and HIV care, while barriers included fear of adverse events, pill burden, and lack of knowledge among healthcare workers and patients. Our study has several public health implications. Despite major losses in the cascade-of-care found in our analyses, the overall initiation and completion of TPT among PLHIV was higher than described in a previous systematic review [11]—which evaluated multiple at-risk populations. The differences in the study populations included in these 2 systematic reviews might explain the difference in findings. Our systematic review was exclusively in PLHIV, who are usually already linked to the healthcare system. In the previous systematic review, the main loss (approximately 28%) occurred in the initial identification and linkage to healthcare step [11], likely because the populations in that review were mainly contacts and immigrants, who were not already linked to the healthcare system. The important losses in the cascade found might be explained by the fragmentation of TB and HIV care. Multiple studies reported that integration of TB and HIV care was an important enabler of TPT [18,38,72,74,76,79,82], while fragmentation of TB and HIV care was identified as an important barrier [34,81]. This suggests that policymakers should work to close the gap between HIV and TB care. An important finding in our review was that the use of LTBI tests was not a barrier to TPT initiation or completion among cohorts that used them. Cohorts that used IGRA, compared to cohorts tested with TST, had a higher percentage of population in initiating (87% versus 73%) and completing (99% and 89%) these tests, but overall TPT initiation and completion was similar, regardless of type of test used. Despite the possible lower sensitivity of IGRAs and TST in PLHIV, previous trials and systematic reviews [2,3,5] have shown that PLHIV with positive LTBI tests benefitted most from TPT, since the risk of TB in PLHIV with a positive LTBI test (TST or IGRA) is 11-fold higher than in PLHIV with a negative LTBI test [5]. Interestingly, TPT recommendation and initiation was higher among cohorts that used LTBI tests; this may reflect providers and patients’ beliefs in prescribing and accepting treatment with evidence of a positive test. For these reasons, we suggest that the use of LTBI tests should be encouraged, not only in high-income countries where it is already part of care, but also in low- and middle-income countries, where this review found numerous reports of its successful use. TPT may provide some benefit in high TB incidence settings if all PLHIV are treated without use of LTBI testing [86,87]. However, the use of LTBI tests can identify those most likely to benefit [5], and treatment without prior LTBI testing might expose PLHIV without TB infection to a nontrivial risk of adverse events [88,89]. Furthermore, the healthcare expenditures for drugs, follow-up visits, and tests including those related to AE, to provide TPT to PLHIV who may not benefit from this could be redirected to strengthening the LTBI cascade-of-care in those (with positive LTBI tests) who will benefit more from TPT. Completing the medical evaluation was considered an important barrier in cohorts that did not use LTBI testing. These cohorts used diagnostic algorithm strategies [4] that rely on symptom screening. However, in the presence of symptoms and/or if the patient is receiving ART, a chest X-ray is recommended before TPT initiation [4]. All these cohorts were from low- and middle-income countries, where chest X-ray services are not commonly accessible. Even where the test is available, the cost often falls on the patient and their family [90] and can be prohibitively expensive. Therefore, the elimination of the financial burden of chest X-rays is essential for TPT scale-up or alternative algorithms using other diagnostic tests to exclude active TB [91,92]. Finally, among the 50 cohorts that provided information on the TPT regimen prescribed, 49 used isoniazid, even though short rifamycin regimens have been available for over 2 decades. TPT completion was low in primary and all stratified analyses, and pill burden and fear of adverse event were reported as barriers for TPT initiation and completion. Certain ART regimens may present drug–drug interactions with rifamycin regimen, especially protease inhibitors. This could explain the lower prescription of rifamycin short regimens by the providers. However, non-nucleoside reverse transcriptase inhibitors (such as efavirenz) and the integrase inhibitors—such as raltegravir or dolutegravir (doubling the dose)—can be coadministered with rifamycins [14]. Increase use of shorter rifamycin-based regimens should be considered, as these may improve TPT completion and are safer, cheaper, and at least as effective as isoniazid regimens [93–99]. This systematic review has a number of limitations. Only 14 of the included cohorts reported all the steps of the cascade-of-care. To include a greater diversity of study settings, we included all 71 cohorts in which at least 2 consecutive cascade steps were reported. This allowed us to calculate the proportion of PLHIV retained in multiple steps of the cascade-of-care from a much larger number of studies, enhancing generalizability. When we compared results of analysis of all cohorts with the 14 studies that included all the steps of the cascade-of-care, results were very similar. Barriers and facilitators were not systematically reported in all included cohorts, so we could not fully understand why the losses and/or retention occurred at each cascade step. All but one of the studies were observational and mostly used convenience sampling or did not describe the population selection. Hence, the majority of studies were judged to have potential selection bias. As a result, we consider the overall quality of evidence to be low, limiting inferences from our findings. Only 3 studies focused exclusively on children, so the pediatric TPT cascade-of-care could not be assessed. The strengths of this review include the large number of cohorts meta-analyzed (N = 70) and the large population of PLHIV (N = 94,011), which allowed us to perform more detailed stratified analyses including country income level, use of LTBI tests, type of LTBI test, and type of clinic. We also evaluated cohorts from different countries, with a wide range of socioeconomic status and resource availability, enhancing the generalizability of our findings.

Conclusions In conclusion, TPT initiation and completion were higher in PLHIV than previously reported for other at-risk populations. Linkage to the health system, clear and consistent evidence from multiple randomized trials of the benefits of TPT, and consistent recommendations by international and national public health authorities might explain this degree of relative success. These lessons should be applied in other groups, particularly in household contacts. Despite this, our analysis of the LTBI cascade-of-care among PLHIV reveals continued important losses. Only 40% of PLHIV eligible for TPT completed this, which is much lower than other care targets in HIV, such as the famous “90-90-90” [100]. Therefore, continued efforts are needed to further improve the LTBI cascade-of-care in this population.

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