Effectiveness and Safety of 9-Month Treatment Regimen for Multidrug-Resistant Tuberculosis in the Philippines

Background: The Philippines has a burden of drug-resistant tuberculosis (DR-TB). One of the key challenges in the programmatic management of DR-TB (PMDT) is the high rate of loss to follow-up (38% in the 2010 cohort). An urgent need for a shorter, more tolerable, less expensive treatment regimen exists. The aim of the operational study is to determine the efficacy and safety of the short treatment regimen among drug resistant TB. Methods: This is a prospective single-arm cohort study evaluating the effectiveness and safety of a shorter 9 - 11-month treatment regimen (9MTR) for rifampi-cin-resistant/multi-drug resistant TB (RR/MDR-TB) in 10 PMDT facilities. All eligible consenting adult patients with rifampicin-resistant TB were enrolled and received the standardized 9-month treatment regimen (9MTR), including injectables, with a follow-up after 12 months of treatment completion. Results: A total of 329 patients were enrolled from July 2015 to December 2016. At the 6th month post-enrollment, 256 (77.8%) of them had cul-ture-negative months of treatment. Conclusion: The 9-month treatment regimen had a high treatment success rate with a favorable safety profile. The loss to fol-low-up was reduced; however, it was still a challenge. The introduction of the 9MTR via operational research had a major impact on building national capacity and infrastructure for the programmatic adoption of a new regimen. Ten PMDT centers received training and experience, created diagnostic pathways, and active drug safety monitoring and management were built.


Introduction
The Philippines is one of the 30 countries with a high burden of tuberculosis (TB) and drug-resistant TB rates according to the World Health Organization (WHO) [1]. In 2018, the country had an estimated annual incidence of 554/ 100,000 [2]. The results of the 2018 Drug Resistance Survey in the Philippines demonstrated 1.8% of the new cases and 16.6% of the retreatment cases to be rifampicin-resistant, and the total estimated incidence of rifampicin-resistant/ multidrug-resistant-TB (RR/MDR-TB) in 20,000 cases [3].
A high proportion of patients were lost to follow-up (LTFU) during drug-resistant TB (DR-TB) treatment due to the following reasons: adverse drug reactions, need to work, personal challenges, geographical barriers, and the long duration of the standard regimen [4]. Loss to follow-up reached 31% for the DR-TB cohort of 2015 [5].
Given the large burden of RR/MDR-TB in the Philippines and the high LTFU rate, there was an urgent need for a shorter, more tolerable, and less expensive treatment regimen. The 9-month treatment regimen (9MTR) with an injectable agent was seen as an alternative treatment option for RR/MDR-TB. This prospective single-arm cohort study was conducted in 10 programmatic management of DR-TB (PMDT) treatment facilities to measure the effectiveness and safety of the 9-month treatment regimen in the Philippines.

Study Population and Setting
The study was conducted in 10 programmatic management of DR-TB (PMDT) treatment facilities. These were selected based on the site inclusion criteria: at least 1 year of experience in managing patients with DR-TB; suitable staff and facilities for close supervision of patients; access to diagnostic and laboratory examinations and a network of TB laboratories; and has expressed commitment to participate in the study.

Study Design and Methodology
This prospective single-arm cohort study evaluated the effectiveness (interim and final treatment outcomes) and safety of the 9MTR with injectable prescribed to patients with RR/MDR-TB who met all the inclusion criteria and none of the exclusion criteria in 10 PMDT treatment facilities. The protocol was approved by the National Ethics Committee of the Philippines (PCHRD, Philippines) and the Lung Center of the Philippines Institutional Review Board, Quezon City Philippines. Patients enrolled had confirmed RR/MDR-TB were FQ-sensitive and had no resistance to injectable agents. All patients have signed the informed consent and have been enrolled from July 2015 to December 2016. Other inclusion criteria were: 1) no previous use of the second-line anti-TB drugs for 1 month or more; 2) at least 18 years old at the time of enrollment in the 9MTR, and 3) willingness to visit the study site during the entire treatment duration of the study or a local treatment site during the continuation phase of treatment and post-treatment follow-up period.
Exclusion criteria for the study were: 1) pregnant or breastfeeding women; 2) age less than 18 years; 3) extra-pulmonary TB, and 4) human Immunodeficiency Virus (HIV) co-infection with a CD4 count of <50.
Before data collection, permission from the respective ethics committee was obtained from the regional health offices where the 10 PMDT facilities were located and from the heads of the PMDT health facilities.
The composition of the short treatment regimen had an intensive phase of 4 to 6 months with kanamycin, high dose moxifloxacin, prothionamide, high-dose isoniazid, clofazimine, ethambutol, and pyrazinamide; and a continuation phase of 5 months with moxifloxacin, clofazimine, ethambutol, and pyrazinamide.
Capreomycin and levofloxacin were used to replace kanamycin or moxifloxacin, respectively in a few selected cases.
The regimen is summarized as: Post-treatment follow-up was done at the end of 6 and 12 months after completing the 9-month regimen to determine the relapse rate.

Data Management and Analysis
Data were collected and reviewed as recorded from DR-TB registers, clinical reporting forms, PMDT medical records including treatment cards, screening forms, patient progress report forms, and TB Medical Advisory Committee presentation forms using a formulated standard data collection tool. These collected data were checked for completeness, quality, and accuracy before they were encoded. Double data entry was done for verification. The interim outcome during the 4 th and 6 th month of treatment were analyzed that served as an important indicator if the effectivity of the short treatment regimen through its conversion of the sputum culture from the initial positive to negative culture. Most importantly a 12-month post follow-up after the treatment was closely monitored to determine its relapse rate among those drug resistant tuberculosis who have been successfully treated with short treatment regimen. provided consent for the treatment (see Figure 1). Of the 329 patients enrolled in the study, final treatment outcomes (Table 3) showed 224 (68.1%) cured, 20 (6.1%) completed, 10 (3.0%) died, 41 (12.5%) loss to follow-up, 33 (10.0%) withdrawn, and 1(0.3%) failed.

Results
All deaths in the study were reported within 24 hours to the Philippines Food   Reasons for withdrawal: refused treatment, ADRs, enrolled in the long-term regimen. 3 Reasons for not being evaluated: unable to submit a specimen for sputum culture, refused treatment. Journal of Tuberculosis Research

Discussion
The introduction of 9-month treatment regimen (9MTR) was first implemented in Bangladesh using a combination of 7 drugs with support from the Damien Foundation and reported treatment outcome in 2010 by Van Deun, et al. [7] In 2015, the World Health Organization recommended the 9MTR for patients diagnosed with DR-TB under operational research conditions for patients who are usually treated with conventional 20 -24 months regimen. At that time, the average treatment success rate for DR-TB cohorts was only 50% worldwide [8].
The study of Van Deun [9], et al. requiring 7 types of drugs with pyrazinamide throughout treatment regimen had given a cure rate of more than 85% and occurrence of major adverse drug reactions were infrequent and manageable. In our study, the treatment regimen that consisted of a combination of 7 first-line and second-line anti-TB medications was essentially the same as the Bangladesh regimen [9] except for the use of high-dose moxifloxacin or levofloxacin instead of gatifloxacin. Pyrazinamide, with sterilizing activity, and clofazimine, a well-tolerated companion drug. [10] [22] were given throughout treatment. The regimen was given for 4 -6 months during the intensive phase, followed by a 5-month continuation of 4 oral medications.
We used both sputum smear tests as well as a culture conversion to determine treatment progress and also used it as an important interim indicator of the efficacy of anti-TB treatment for RR/MDRTB [11] [12]. In the study, early sputum culture conversion was achieved among 79% at the end of the 4th month and 78% at the end of the 6th month [13].
Adverse drug reactions were experienced during the initial 6 months by a majority of patients. Gastrointestinal events were common symptoms. In our study, the frequency of vomiting and nausea occurred in two-thirds of our patients during the first 6 months and has been managed through appropriate treatment actions, including counseling and ancillary medications.
Ototoxicity was predominantly associated with the use of parenteral anti-tuberculous agents like aminoglycosides and aminopeptides [14]- [19]. In the study, the frequency of ototoxicity was among the top 10 adverse events. Among  [9]. In our study, 10 (3%) died during the treatment, 7 (70%) died during the intensive phase, and 3 (30%) during the continuation phase. In all of these patients, preceding culture results had been negative.
The treatment success rate of (>80%) and the low relapse rate of (<1%) in our study were favorable as compared to a longer treatment regimen which had a 50% success rate worldwide (for the 2013 cohort) [20]. In the Philippines, the treatment success rate for DR-TB patients placed on a longer regimen was 41% in 2000, [21] and slightly increased to 55% in 2015 [5]. The treatment success rate under a short treatment regimen in our cohort was similar to the one reported for Niger [22] and South Africa [23] that had 89.2% and 78.8% respectively.
While it was a requirement for all clinical trials, it was therefore considered a best practice for operational research studies to follow up with patients after the end of the treatment for a 6-or 12-month period. Such observation allows to capture early replacements and to confirm treatment success rate results, especially for patients who did not have culture confirmation at the end of the treatment (people who registered as treatment completed). In our study, we strived to monitor patients for 12 months, however, it was difficult to obtain patient Active drug pharmacovigilance was part of the protocol implementation and all adverse events were documented. However, the study has limitations. First, it was an operational study done only in 10 selected facilities and protocol-guided management was strictly followed. Second, the turn-around time of the line probe assay result came longer than the expected schedule resulting in a limited number of enrolled patients in the study. Our study did not administer genotyping or DNA fingerprinting to differentiate the origin of acquired drug resistance TB. Given the low incidence of HIV co-infected in the country which is <1%, we need further study as to what extent this short treatment regimen is effective for the HIV-infected population.

Conclusion
The effect of the short treatment regimen for the treatment of multidrug-resistant tuberculosis showed a high treatment success rate with a favorable safety profile.
Loss to follow up was much reduced but still is a challenge. The introduction of 9MTR via operational research had a major impact on building national capacity and infrastructure for programmatic adoption of the new regimen. Ten centers