Tuberculosis: Development of New Drugs and Treatment Regimens

Article history: Tuberculosis (TB) still becomes a public health crisis. Drug-resistant TB (DR-TB) Received 06 January 2021 becomes a concern as the increasing DR-TB cases in countries with high TB burden. Received in revised form 22 January The 2017 World Health Organization (WHO) guideline recommended a combination of 2021 TB treatment consisting of 2 months of intensive phase with isoniazid (H), rifampisin Accepted 27 January 2021 Available online 30 January 2021 (R), pyrazinamid (Z), and ethambutol (E), followed by 4 months of continuation phase


INTRODUCTION
Tuberculosis (TB) continues to be a public health crisis worldwide. Globally, an estimated of 10 million TB cases is reported with 1.2 million mortality cases in 2019. 1 The number of drug-resistant TB (DR-TB) cases increase every year. Combination of rifampisin (R), isoniazid (H), pirazynamide (Z), ethambutol (E) with or without streptomycin (S) is a standardized first line regimen in drug-sensitive TB (DS-TB). Multi-Drug Resistant TB (MDR-TB) is defined as TB caused by strains of Mycobacterium tuberculosis which are resistant to at least R and H, two of the most potent first line anti-TB drugs. 2 Indonesia is one of 30 countries with high TB burden in the world and is in the 2 nd rank in the world with 845,000 TB cases, while DR-TB cases is in the 5 th rank with 24,000 cases in 2019. 1 TB treatments aim to cure patients, prevent complications and death, avoid recurrence, reduce the potential for transmission to susceptible people, and limit the emergence and spread of drug-resistant strains.
Current treatment for DS-TB, which consists of isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) for 6 months (2HREZ/4HR), shows high cure rates at around 90 -95%. 3 Anti-TB drugs also cause side effects from mild to severe. Problems with compliance, sub-optimal drug levels, and tolerability can lead to resistance. Shorter and more tolerated regimens are desperately needed to increase adherence and reduce loss to follow-up both DS-TB and DR-TB cases. 4 Effectiveness of TB treatment depends on combinations of several bactericidal drugs and sterilizing activity in an adequate duration, to keep antimicrobial efficacy while preventing drug-resistant mutants and achieve permanent cure. 5 New TB drugs and regimens are urgently needed to improve cure rates and shorten the treatment of both drug-susceptible (DS) and drug-resistant (DR) TB (currently at least 6 to 9 months respectively). Regimens that consist of entirely new drugs will be an important therapeutic advance, because they will reduce the need of drug-susceptibility testing (DST). 6 The current development of shorter and simpler treatments with a combination of new drugs and existing drugs requires detailed information about the safety and toxicity of each drugs; potential drug interactions; potential drug resistance when used for treatment; and its use in certain patients such as HIV, pregnant women, and children. 7 The current research is underway to develop a shorter, more effective, safer, and more tolerated combination of treatments. 3  In patients who need re-treatment, category 2 WHO regimens should no longer be given, the choice of regimen is considered based on DST.
The 2016 ATS/IDSA guidelines stated differently than the 2017 WHO guidelines in terms of duration of treatment in the continuation phase. Sputum culture examination results at the end of intensive phase (2 months) are related to the possibility of recurrence after the completion of TB treatment. Patients with cavity on chest X-ray at the initial treatment and positive cultures after 2 months of treatment are risk factors of relapse by 20%, compared with pulmonary TB patients without these risk factors by 2%. Based on this consideration, the expert team's opinion was to extend the continuation phase with H and R for 3 months to reduce the possibility of relapse. 12 High doses of rifampicin and rifapentine have been studied to shorten TB treatment. In the PanACEA MAMS-TB-01 trial, rifampicin 35 mg/kg per day which added to standard doses of isoniazid, pyrazinamide, and ethambutol yielded an improved hazard ratio for stable culture conversion in liquid medium over 12 weeks (hazard ratio 1.75, 95% CI 1.21-2.55). However, the effect on culture status at 8 weeks using solid medium (10% positive vs 15% in controls) was predicted to cause a relapse rate of 13% if only administered for 4 months. In studies of rifapentine 1.200 mg once a day proposed for a phase 3 trial (NCT02410772) also resulted in 10% of patients with positive cultures using solid medium at 8 weeks in a phase 2 trial. Regimens resulting in 13% relapse cases are not likely to be accepted by TB control programmes. 6 The main adverse effect was hearing impairment on 46/106 (43%) patients. 14 Standardized 12-month treatment for MDR-TB was highly effective and well tolerated in patients not previously exposed to secondline drugs in Nigeria, and the main adverse effects were vomiting (26.2%) and hearing impairment (20%) but no treatment had to be stopped and no relapse cases. 15 Currently, the used of Mfx in STR are still debatable due to the presence of prolonged QT as an adverse effect. A study shows that Mfx is more likely to cause QTc prolongation than the other fluoroquinolones (FQs), although FQ is likely to be the most effective drug against MDR-TB. The risk of QTc prolongation with the FQs is higher when there are electrolyte imbalances and when other QTc prolonging medications are used. 16

Grouping Anti-Tuberculosis Drugs and Composing Individual Regimen
WHO has changed the grouping of drugs to make an individualized regimen based on the efficacy hierarchy of each drug. This change was made based on scientific evidence obtained from quality research results.
Bedaquiline did not appear to be one of the main drugs of choice in making a combination of DR-TB treatment at the beginning of the 2008 DR-TB guidelines, but was changed in the 2020 guidelines as bedaquiline becomes the main drug of choice. Kanamycin and capreomycin, which were originally used as the main drugs in making DR-TB treatment regimens, are no longer recommended as one of the DR-TB drugs in DR-TB regimens. Table 1 below is a grouping of TB drugs according to their hierarchy and the steps to make regimens.
Injection drugs are no longer a priority in making individualized MDR-TB regimens. Kanamycin and capreomycin are no longer recommended, thus an entirely oral regimen is the preferred choice by patients. Three drugs such as fluoroquinolone (levofloxacin or moxifloxacin), bedaquilin, and linezolid are strongly recommended for use in individualized regimens. In MDR/RR-TB patients on longer regimens, a total treatment duration of 18-20 months is suggested for most patients; the duration may be modified according to the patient's response to therapy. In multidrug-or rifampicinresistant tuberculosis (MDR/RR-TB) patients on longer regimens, the performance of sputum culture in addition to sputum smear microscopy is recommended to monitor treatment response. It is desirable for sputum culture to be repeated at monthly intervals. 9 The guideline in Indonesia recommended 5 drugs in the intensive phase and 4 drugs in the continuation phase. • Build a regimen using 5 or more drugs • Choice of drugs is contingent on capacity to appropriately monitor for significant adverse effects, patient comorbidities, and preference/values (choices therefore subject to program and patient safety limitations) • In children with TB disease who are contacts of infectious MDR-TB source cases, the source case's isolate DST result should be used if an isolate is not obtained from the child. • TB expert medical consultation is recommended (ungraded good practice statement) Step 1: Choose 1 fluoroquinolone Levofloxacin Moxifloxacin Step 2: Choose both of these prioritized drugs Bedaquiline Linezolid Step 3: Choose both of these prioritized drugs Clofazimine Cycloserine/ terizidone Step 4: If a regimen cannot be assembled with five effective oral drugs, and the isolate is susceptible, use one of these injectable agents

Amikasin Streptomycin
Step 5: If needed or if oral agents preferred over injectable agents in Step 4, use the following drugs Delamanid Pyrazinamide Ethambutol Step 6: If limited options and cannot assemble a regimen of five effective drugs, consider use of the following drugs Ethionamide atau prothionamide Imipenem-cilastatin/ clavulanate or meropenem/ clavulanate p-Aminosalicylic acid High-dose isoniazid The following drugs are no longer recommended for inclusion in MDR-TB regimens Capreomycin dan kanamycin Amoxicillin/clavulanate (when used without a carbapenem) Azithromycin and clarithromycin Both ATS (2019) and WHO (2020) guidelines recommended new drugs or repurposed oral agents with greater efficacy and do not recommend the use of injection drugs. 9,17 Clinical step to make an individualized regimen recommended by ATS in determining certain drugs is presented in Table 2 below.
Fluoroquinolones (levofloxacin or moxifloxacin), bedaquilin, and linezolid are recommended as the main drugs in individualized regimens. Delamanid is a drug currently used to complete treatment regimens and when drugs in groups A and B can not be used ( Table 1). The use of bedaquiline is acceptable for children aged at least 6 years old and delamanid is for 3 years old children. Further study for bedaquiline is needed to determine optimal pharmacokinetic in children, cost effectiveness, and optimization of the duration in both adults and children, while delamanid is needed to be studied for its role in MDR TB regimens in children (pharmacokinetics/pharmacodynamics), patients with HIV, pregnant women, drug resistance mechanisms, and the optimization of the duration both in adults and children. Knowledge about the safety of bedaquiline and  delamanid in pregnant and nursing women is very rare, thus it is recommended to use individualized regimens by using drugs with a guaranteed safety profile. The results of treatment during pregnancy and supervision after childbirth are also needed to be documented to provide information on MDR-TB treatment recommendations in future pregnancy. 9 American Thoracic Society (ATS) have grouped the drugs list used for DR-TB, including a list of not recommended drugs. Table 3 below is a recommendation of MDR TB drugs. 17 The guideline of DR-TB recommended by ATS Although WHO recommends evaluation of drug resistance, their guideline accepts that globally empirical regimens will continue to be used. ATS/CDC/ERS/IDSA guideline requires microbiological data to create a regimen suitable for the individual patient's strain of tuberculosis. 17 Recommendations regarding the composition, has demonstrated a higher bactericidal activity than linezolid, as well as perhaps a potential sterilising activity. The whole blood bactericidal activity of sutezolid 600 mg twice daily is higher than linezolid 300 mg once daily. Although EBA of sutezolid is significantly lower than that of the standard regimen, a whole blood bactericidal activity assay has demonstrated its synergistic activity with pyrazinamide. Sutezolid does not appear to cause QT interval prolongation or bone marrow suppression, although there are still concerns regarding potential neurotoxicity and hepatotoxicity. 18 No hematological toxic effects were reported in phase 1 trials for sutezolid 600 mg twice a day for 28 days, which was thought to reduce the inhibition of mitochondrial protein synthesis. Sutezolid dose of 600 mg twice a day and 1,200 mg once a day were well tolerated and showed sputum EBA in patients with TB. 7

Repurposed Drugs
The repurposed drugs have been used for MDR-TB and XDR-TB treatment while being evaluated of new DR-TB drugs and regimens. Fluoroquinolones, kanamycin, amikacin, clofazimine, linezolid, carbapenem, and amoxicillin/clavulanic acid are repurposed drugs. The 3 rd and 4 th generation of fluoroquinolones (levofloxacin, moxifloxacin, and gatifloxacin) are often used for the treatment of H monoresistant TB and MDR-TB, which are the most important components in second-line drugs. 19,20 As fluoroquinolone is widely available and is used for treating several infectious diseases, it is important to consider the potential for resistance in patients who are not diagnosed with TB and treated with fluoroquinolone. 21 The antileprosy drug, clofazimine, has shown sterilising activity and treatment-shortening potential. A new rimino-phenazine, TBI-166, has entered phase 1 trials and will hopefully not produce skin discolouration, a common adverse effect of clofazimine. 3 Linezolid has been reported as a failing regimen on 39 XDR-TB patients with sputum culture conversion on solid media was 35% after 2 months and 87% after 6 months. 82% patients experienced linezolid toxicities, resulting in 3 patients permanently discontinued from linezolid. Based on these results, research on linezolid was conducted to identify the optimal dose to minimize toxicity without reducing their efficacy. 22 Linezolid was effective in achieving culture conversion, but 82% of patients experienced adverse effects such as myelosuppression, peripheral neuropathy, and optic neuropathy. Patients who received 300 mg per day experienced fewer adverse effects than 600 mg per day, but it can cause resistance. 3 Carbapenem may play a role in MDR-TB regimen based on in vitro activity and case reports. Initial trials of faropenem and meropenem are ongoing. Sulfonamides have also been proposed as anti-TB drugs based on the sensitivity in vitro, but no prospective trials have been conducted. Several prophylactic cotrimoxazole studies in HIV patients in Africa have reported no effect on TB. 6 Meta-analyzes and systematic reviews of carbapenem use (ertapenem, imipenem, meropenem) for MDR-TB and XDR-TB treatment showed good tolerance and safety records, but the absence of active oral formulations and the need for combination of amoxicillin and clavulanic acid (which keeps meropenem and carbapenems from βlactamases) reduced the activity of carbapenems. 3  . Updated recommendations will be published in the first quarter of 2020. 21 Rifapentine is given once in a week with combination of isoniazid for LTBI. 12 ATS recommends LTBI treatment for people in contacts with patients with MDR-TB using a later generation of fluoroquinolone or single therapy using 2 nd line drug for 6 to 12 months of treatment, based on the drug susceptibility of the source-case Mycobacterium tuberculosis isolate, followed with observation alone (conditional recommendation, very low certainty in the evidence). If there are evidence of increased toxicity, adverse events, and discontinuations, pyrazinamide should not be routinely used as the second drug. 17 Clinicians and patients have long desired shorter, more tolerable, and safer alternatives for treatment of LTBI rather than standardized daily isoniazid for 9 months or more. In 2011, the phase 3 TB TC Study 26 (NCT00164450), undertaken in 7,731 participants, showed non-inferiority of weekly rifapentine and isoniazid (given for 3 months), when compared with 9 months of daily isoniazid. Rifapentine is still unavailable in most countries worldwide. So far, no data are available from phase 3 trials to eradicate latent infection due to drug-resistant Mycobacterium tuberculosis, though two trials are underway assessing 6 months of daily levofloxacin versus placebo, and a large trial will soon begin assessing 6 months of daily delamanid versus 9 months of daily isoniazid, in adults and children. Drugresistant LTBI is a high priority for the control of the growing DR-TB threat. Table 4 below summarized the trials that are being and will be conducted to examine chemoprophylaxis for individuals exposed to TB and DR-TB, which are being prepared or will be performed as soon as possible. 3

CONCLUSION
The treatment of DR TB has grown fast over the past few years. A new, shorter MDR-TB regimens and an increase in the availability of new or repurposed drugs is needed. Management of TB and DR-TB will be updated any time according to the latest findings to evaluate and improve the effectiveness of current treatments. The treatment of latent TB is one of the efforts to control TB to reach the end of TB 2035. Therefore, the development of new drugs for the treatment of LTBI is also very important.