How are high burden countries implementing policies and tools for latent tuberculosis infection? A survey of current practices and barriers

Abstract Background and aims Despite the World Health Organization (WHO)'s updated guidelines on tuberculosis (TB) preventive treatment, the scale‐up of TB preventive therapy remains low in many high‐burden countries (HBCs). We conducted a survey to better understand the current status of policy implementation and barriers for scale‐up. Methods Survey questions pertained to HBCs' current latent TB infection (LTBI) screening and treatment strategies, and the availability of LTBI tests and newer treatments (eg, isoniazid/rifapentine [3HP]). The 19‐question survey was piloted and sent out via email in June 2019 as a protected Microsoft Word document to contacts [National TB Program (NTP) staff, researchers, and health officials] in the 30 TB HBCs. Responses were accepted until February 2020. Results Thirty‐seven completed surveys from 24 HBCs were received. Respondents from five countries (Brazil, Lesotho, Mozambique, Russia, Zambia) reported having LTBI guidelines that are fully implemented. Among respondents who indicated their country currently has no LTBI guideline implementation (Angola, China, DRC, India, Indonesia, Kenya, Myanmar), the most often cited barrier to implementation was the prioritization of active TB over LTBI management (n = 5, Angola, China, DRC, India, Kenya). Of the 16 countries in which respondents reported using purified protein derivative (PPD), 9 reported having experienced a PPD shortage within the past year (from time of survey). Respondents from six countries reported currently using Interferon‐gamma Release Assays (IGRAs) in their NTP, and 13 cited high cost as a barrier to IGRA use. Lastly, rifapentine was stated not be available in 8 HBCs. Conclusion This survey indicates limited implementation of WHO LTBI guidelines in HBCs and provides some insight into barriers to implementation, including shortage of products (eg, PPD), high costs (eg, IGRAs), and lack of regulatory approval of newer treatments (eg, rifapentine). Thus, we should work towards price reductions for LTBI tests and treatments, and the development of tests that can be more easily implemented at peripheral healthcare levels.


| INTRODUCTION
Tuberculosis (TB) continues to be a major global health concern, having resulted in an estimated 1.5 million deaths globally in 2018 -more than any other infectious disease. 1 Based on recent re-estimations, approximately 23% of the global population has latent TB infection (LTBI), 2 meaning that they have an immune response to Mycobacterium tuberculosis (Mtb), but only a small proportion will progress to active TB. 3 Given the limitations of current evidence regarding optimal LTBI management, national policies regarding testing and treatment remain varied and inconsistently implemented. In particular, a review of 98 countries (including both high and low burden countries) found that algorithms for LTBI testing were inconsistently implemented, as were procedures for excluding active TB before initiating preventive treatment. 4 While active TB continues to be a high priority for high-burden countries (HBCs), these countries are starting to roll out TB preventive therapy. To this end, in 2020, the World Health Organization (WHO) issued updated guidelines on TB preventive treatment (module 1 of the 2020 WHO consolidated guidelines on TB), which include updated recommendations for HBCs. 5 The guidelines comprise recommendations for targeted testing and treatment of people living with HIV (PLHIV), adults and children under 5 years of age who are household contacts of pulmonary TB cases, and HIV-negative risk groups such as patients with silicosis, those on dialysis, or those receiving organ or haematological transplants. 5 Importantly, as these groups are at increased risk of progression to active TB disease, the updated guidelines recommend targeting these groups for LTBI screening and treatment in all settings, independent of TB prevalence. 5 Moreover, the 2020 guidelines state that systematic LTBI testing and treatment can also be considered in other risk groups, such as healthcare workers, prisoners, or the homeless, regardless of TB burden (as opposed to primarily in low-burden settings as indicated in the 2018 LTBI management guidelines). 5 The global TB community has ambitious targets for preventive therapy. The first-ever United Nations General Assembly high-level meeting on TB endorsed an ambitious political declaration, which commits to offering preventive therapy to at least 30 million people, including 4 million children under 5 years of age, 20 million other household contacts of people affected by TB, and 6 million PLHIV, by 2022. 6 However, there are a myriad of challenges associated with both diagnosing and treating LTBI, 7,8 particularly in the HBC context, including the logistical barriers associated with requiring patients to return for Tuberculin Skin Test (TST) results to be read, 9 and widespread Bacille Calmette-Guérin (BCG) vaccination in HBC countries leading to high numbers of false positive TST results. 10 Further challenges include a lack of new funding for LTBI programs, infrastructure requirements, 5 shortages of products such as purified protein derivative (PPD), 11 the unavailability of newer LTBI drugs (eg, rifapentine) in some countries, 12,13 and the unavailability of childfriendly LTBI treatment formulations. 14 In light of the abovementioned persisting challenges for LTBI screening and treatment in HBCs, it is of interest to investigate the extent to which HBCs are currently planning or able to implement the WHO's updated guidelines on LTBI management, and which barriers they face. This study, therefore, presents the results of a survey of HBC National TB Programs (NTPs), aiming to identify challenges experienced in HBCs with regards to the implementation of LTBI policies and tools.

Survey questions included both open-ended and predefined
response options, and where predefined options were given, a "specify other" field was always provided to allow any additional responses not captured in the given options. The questions were prepared and piloted among four respondents in May 2019, and pertained to the HBC's current LTBI screening and treatment strategy; the availability of Interferon-gamma Release Assays (IGRAs), PPD, and various treatment regimens; and budget plans for future rollout of tests or treatments.
The pilot-phase respondents included health ministry officials and NTP staff, who were asked to provide their input on any unclear questions.
As the questions were generally well understood, the survey was sent out in June 2019 (via email, as a protected Microsoft Word document) to HBC contacts, including NTP staff, researchers, and health officials.
Contacts were informed of the purpose of the survey, and that the results would be summarized by country, with all participant names remaining anonymous and being treated as confidential. Up to four waves of reminders were sent to contacts that had not yet responded to the survey, with the last wave of reminders sent in November 2019.
Responses were accepted until February 2020. Pilot-phase responses were also included in the final analysis.
Survey data were extracted using a data extraction form created in Microsoft Excel (version 16.34). Data are presented descriptively by country. In the case of countries with multiple responses, all responses are taken into account in the presentation of data for that country (eg, if a respondent indicated financial barriers to LTBI guideline implementation and a second respondent from the same country indicated lack of staff as a barrier, then both are listed as barriers to LTBI guideline implementation for that country). In the case of directly conflicting responses between two respondents from the same country (eg, having vs not having a policy for 3HP implementation), the conflicting responses are indicated (eg,   Table 1.

| LTBI guideline implementation
Respondents of only five countries reported having national LTBI guidelines that are fully implemented (ie, all recommendations in the guidelines are carried out; Brazil, Lesotho, Mozambique, Russia, and Zambia). Respondents from seven countries indicated that their NTP does not have national LTBI guidelines (Angola, China, DRC, India, Indonesia, Kenya, Myanmar), and respondents from the remaining 12 countries reported that LTBI guidelines exist in their NTP, but that these are not fully implemented. Among the 17 countries for which respondents reported that national LTBI guidelines exist (either fully or partially implemented), these guidelines were available in the literature (scientific papers or governmental policy documents) for 14 countries (Ethiopia, 14,16 Lesotho, 17 Mozambique, 18 Nigeria, 19 South Africa, 20 Tanzania, 21 Zambia, 22 Zimbabwe, 23 Thailand, 4 Cambodia, 4 Philippines, 24 Vietnam, 4 Brazil, 25 and Pakistan 4 ). LTBI management guidelines for all of these countries are outlined as part of their overall national TB guidelines, except in the case of Brazil, where LTBI guidelines are provided in a separate policy document specific to LTBI. 25 Documents outlining national policies specific to the management of LTBI were not found for Liberia, 4 Bangladesh, 26 or Russia.
Among respondents who stated their countries lack LTBI guidelines, the most often cited barrier to guideline implementation was the prioritization of active TB over LTBI management (n = 5, Angola,

| LTBI screening and treatment practices
Considering the risk groups in which LTBI screening is recommended  Table 4. Respondents from nine countries reported having experienced a PPD shortage within the past year, while respondents from four countries (Bangladesh, Ethiopia, Myanmar, and Nigeria) stated not knowing whether a shortage was experienced. Of the three countries whose respondents did not report a PPD shortage (China, Indonesia, and Mozambique), two (China and Indonesia) reported using locally-manufactured PPD. PPD shortage status by country, as reported by the respondents, is shown in Table 4.
Of the nine countries whose representatives reported experiencing a PPD shortage, most (n = 5, Brazil, India, Pakistan, Zimbabwe, and Thailand) cited delayed or insufficient supply from the manufacturer as the main reason for the shortage. Additional reasons mentioned included not having a supplier (Philippines), the supplier ceasing importation (Vietnam), and the supplier's authorization from the manufacturer not being renewed (Pakistan, manufacturer: Sanofi Pasteur).
In the case of Kenya, it was also mentioned that staffs are sometimes not aware when PPD does become available, leading to further delays in implementation.
Representatives from 11 countries were able to provide cost estimates for PPD in their NTPs. Costs per patient are shown in USD in   Table 5. Respondents from Russia and the DRC were the only ones not reporting any barriers to IGRA implementation.
Respondents from 12 countries provided estimates of how many individuals their NTP planned to screen for LTBI in 2019, via any test (see Table 6), however, only respondents from Thailand and Russia were able to provide estimates of how many are to be screened specifically with IGRAs. Cost estimates for IGRAs were also provided only from Thailand and Russia, reporting costs of 45 USD and 106 USD per patient, respectively.

| 3HP implementation
Respondents from 13 countries reported having a policy on the implementation of the 3HP regimen (see Table 7). Respondents from most countries (n = 15) reported the high cost of the regimen as a barrier to implementation (including both countries with and without a current policy for 3HP use), and, as reported by the respondents, Rifapentine is not currently registered in eight countries. Other barriers to 3HP implementation in NTPs include concerns about drug-drug interactions between Rifapentine and antiretrovirals (n = 7) and adverse effects of the regimen (n = 5).
Again, respondents from the DRC and Russia did not report experiencing any barriers to implementation. Barriers reported in each NTP are shown in Table 7 Screening tool/treatment regimen is used in this risk group in NTP. (a) May include the use of nontechnological "tools," such as symptom scores or questionnaires; (b) CXR where available, but clinical screening only is the more common scenario; (c) Will gradually expand 3HP and 3RH implementation; (d) TST and CXR where available, especially in private facilities, but clinical screening only is the more common scenario; (e) Rifapentine in trial phase in selected areas. a These represent risk groups in which LTBI screening is recommended in high burden settings as per the 2018 WHO guidelines (in effect at the time of the survey), and remain unchanged in the updated 2020 guidelines, which now supersede those from 2018. 5  Risk group is not screened in NTP. Risk group is screened/screening tool/treatment regimen is used in this risk group in NTP. financial resources or supply of LTBI screening tools, HBCs may restrict their screening efforts to certain priority risk groups, and considerable additional resources and support may be required for HBCs to reach full guideline implementation in light of the expanded recommendations.

T A B L E 3 LTBI screening tools and treatment regimens used in other risk groups targeted for LTBI screening in 24 high TB burden countries according to survey respondents
Furthermore, regarding the use and availability of PPD, respondents from nine countries reported having experienced a PPD shortage within the past year. In addition, the challenge of ensuring high PPD quality also underlines the need to invest further in the development of new LTBI tests that are non-PPD-based. It also indicates a need for further studies on the diagnostic performance of already available non-PPD-based skin tests, such as the Diaskintest and C-Tb, to provide an evidence-base for their potential as alternatives to PPDbased tests.
Regarding the use of IGRAs as an alternative to the TST for LTBI testing, it is important to note that respondents from the majority of countries surveyed (13 out of 24) report financial barriers as a major hindrance to IGRA implementation. To address this, in December 2019, the Global Drug Facility included QFT-Plus on its catalog, at a GDF-negotiated price of $15.90 per test for HBCs. 27 However, beyond just unit costs, respondents from many countries also reported the challenges of specimen transport and the lack of laboratory infrastructure as significant barriers to the use of IGRAs in their NTP. This requirement for laboratory facilities for IGRA implementation is also underlined in the 2020 WHO guidelines on TB preventive treatment as an ongoing operational barrier faced by countries with regards to LTBI management. 5 This highlights the importance of continued efforts to develop new LTBI testing tools that do not require significant laboratory facilities or highly trained personnel, and that can be implemented at the peripheral healthcare level (other than the TST).
Given existing ESAT6/CFP10-specific skin tests such as C-Tb and the Diaskintest, 28 However, as called for in a civil society statement released at the 2019 Union World Conference on Lung Health in Hyderabad, India, 13 it is imperative that the price of the regimen be further lowered.
Financial barriers aside, increased efforts must also be made to remove the administrative barriers to 3HP implementation that F I G U R E 1 Costs of purified protein derivative (PPD) per patient (USD) in high-TB-burden countries In initial stages of pilot studies of implementation.
Barrier experienced in NTP ARV Antiretrovirals. Unsure if barrier is experienced in NTP DDI Drug-drug interactions.
(a) Currently updating national strategic plan, 3HP will be budgeted; (b) 3HP is in the process of being procured, and will run as a pilot before nation-wide roll out.
a Multiple respondents per country with differing responses regarding status of 3HP policy.