Clinical outcomes with all-oral regimens in patients of drug-resistant tuberculosis: A prospective study in a tertiary hospital in North India

doi:10.21203/rs.3.rs-5309694/v1

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Clinical outcomes with all-oral regimens in patients of drug-resistant tuberculosis: A prospective study in a tertiary hospital in North India

https://doi.org/10.21203/rs.3.rs-5309694/v1

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Objective:

The main aim of this study is to provide therapeutic outcomes with bedaquiline-based all-oral regimens of drug-resistant tuberculosis (DR-TB).

Methods: A prospective observational study was conducted from August 2022 to March 2024 and patients of DR-TB on all-oral regimens were enrolled.

Results:

Seventy-three patients from long-oral (LO) regimens and 15 from the short-oral (SO) regimen were followed up at 6 months. Sixty-two (84.9 %) patients of LO, and 11 (67.9 %) patients of SO regimen achieved microbiologic improvement in one sample. Clinical improvement occurred in the majority. Forty-five (60.8 %) patients of LO and six (35.3%) patients of SO regimen required treatment modification, and the major reason was intolerability due to peripheral neuropathy. Skin pigmentation (43.8%), anemia (35.6%), and thrombocytopenia (26%) were other common adverse events (AEs), and optic neuritis occurred in two patients in the LO regimen. Hepatitis and thrombocytopenia occurred commonly with regimens combining bedaquiline and delamanid. Linezolid dose was reduced in 45.2% and the drug was replaced in 17.8%, commonly by pyrazinamide and delamanid.

Conclusion:

Interim microbiological outcomes with all-oral regimens of DR-TB were favorable. Extended monitoring is needed to assess the sustenance of treatment effect. AEs such as peripheral neuropathy are a major challenge and emphasize the need for newer regimens with better safety profiles.

Drug-resistant tuberculosis

bedaquiline

delamanid

linezolid

peripheral neuropathy

all-oral regimens

Favourable microbiologic outcomes were achieved over 6 months with all-oral regimens of drug-resistant tuberculosis

In nearly half of the patients, the regimens had to be modified due to intolerability, mainly peripheral neuropathy

Cardiotoxicity was not a concerning adverse event.

Tuberculosis caused by Mycobacterium tuberculosis (M. Tb) is a major global health issue. In 2021, the disease affected 10.6 million people globally and claimed 1.6 million lives. [1]

Drug-resistant tuberculosis (DR-TB) occurs when M. Tb develops resistance to one or more antitubercular drugs. Improper drug selection, use of monotherapy, and poor adherence to therapy are the factors that promote the development of DR-TB. [2]Multidrug-resistant TB (MDR-TB) is defined as resistance in M. Tb to isoniazid (H) and rifampicin (R) which are the core first-line antitubercular drugs. Rifampicin-resistant TB (RR-TB) is the state in which the bacteria is resistant solely to rifampicin. Pre-extensive drug-resistant TB (Pre-XDR TB) is defined as MDR-TB with additional resistance to any fluoroquinolone [2]

India is the major contributor to tuberculosis, drug-resistant tuberculosis, and deaths due to tuberculosis. Nearly 28% of the incident tuberculosis, 26 % of DR-TB burden, and 36 % of total TB deaths were from India in 2021. [1,3]

MDR/RR-TB management previously involved second-line drugs like injectable aminoglycosides. To reduce the distress of daily injections of aminoglycosides and to avoid the potential aminoglycoside toxicity such as hearing loss and nephrotoxicity, the World Health Organization (WHO) has endorsed all-oral regimens that include the newer antitubercular drugs such as bedaquiline and delamanid among others.[4] These guidelines have been incorporated in the Programmatic Management of Drug-resistant Tuberculosis (PMDT) under India's National Tuberculosis Elimination Program (NTEP). [2] According to these guidelines, MDR-TB patients should be shifted to all-oral regimens containing bedaquiline unless contraindicated. [2] Shorter bedaquiline based nine-month regimens are preferred in patients of age more than 5 years and body weight of 15kg or more with less extensive pulmonary disease, milder forms of extrapulmonary tuberculosis, and in the absence of resistance to fluoroquinolone or high dose isoniazid. For DR-TB patients who are excluded from shorter oral bedaquiline-containing regimens, the longer five-drug-based regimen of 18-20 months duration is recommended. [2]Notwithstanding the type of regimens, the evidence on the clinical outcomes with all-oral regimens is limited. [5,6] Prospective studies on all-oral regimens of DR-TB are scarce, particularly from the Indian continent. Largely unexplored are the regimen-specific intolerability and the modifications required subsequently in therapy.

The main aim of the present study is to provide real-world evidence on the therapeutic outcomes with all-oral regimens of DR-TB in North Indian patients.

Study design: This was a prospective observational study conducted in the Department of Respiratory Medicine and Department of Pharmacology in a tertiary hospital in North India from August 2022 to March 2024.

Inclusion criteria: All patients of DR-TB on oral-only regimens who gave consent to participate were included.

DR-TB was diagnosed depending on the Xpert MTB/RIF assay which is a rapid test for detecting Mycobacterium tuberculosis and rifampicin resistance. Xpert MTB is a cartridge-based Nucleic Acid Amplification Test (CBNAAT) for detecting M. Tb.[2] Detection of rifampicin resistance was followed by line probe assay (LPA) for first and second-line drugs and liquid culture - Drug Susceptibility Test (LC-DST).

Exclusion criteria:

1. Patients of DR-TB who refused to participate

2. Patients of DR TB patients on any injectable anti-TB drug

3. Patients of DR-TB with HIV co-infection.

4. Patients with drug-sensitive TB

Outcomes measured:

1. Microbiological improvement as assessed by smear or culture conversion for M. Tb in at least one sample over 6 months of therapy.

2. Clinical improvement in symptomatology as reported by the patients.

3. Intolerability assessed as adverse events (AEs) with all-oral regimens for DR-TB.

4. Reasons for the modification of the initial DR-TB regimen.

Patients were started on all-oral longer or shorter regimens endorsed by WHO and recommended by the NTEP, India. [2] Briefly, the regimens are described below:

A longer oral (LO) regimen included 6 months of Bedaquiline (Bdq), levofloxacin (Lfx), or moxifloxacin (Mfx), linezolid (Lzd), Clofazimine (Cfz), and Cycloserine (Cs) followed by 12 months of Lzd, Lfx/Mfx, Cfz and Cs. Bedaquiline was extended beyond 6 months based on clinical response and on a case-by-case basis. In cases of resistance to fluoroquinolone, drugs such as delamanid (Dlm), pyrazinamide (Z), or ethambutol (E) were added as the fifth drug as recommended by the guidelines and considering the availability of drugs at the local DR-TB center. [2]

The shorter oral (SO) regimen consisted of 4 months of Bdq, Lfx, Cfz, Z, E, high dose isoniazid (Hh), ethionamide (Eto), and 5 months of Lfx, Cfz, Z, E. Bdq was extended up to 6 months if needed. In case of the development of resistance to fluoroquinolone or Hh, the patient was shifted to the LO regimen.[2]

Sample size:

In the absence of similar studies from India and considering the feasibility issues, the study aimed to provide 6-month treatment outcomes for at least 75 patients of DR-TB. Considering a high attrition rate of 30-35% as per the experience of investigators, 100 patients of DR-TB were included.

Data collection:

Baseline characteristics, co-morbidities, findings of LPA, culture sensitivity reports, routine blood investigations, chest X-ray findings, and drugs prescribed for DR-TB were recorded in a case report form. Patients were followed up at 1 month, 3 months, and 6 months to record clinical and microbiological improvement. Adverse events (AEs) and reasons for modifications in the regimen over 6 months of therapy were noted.

Statistical analysis:

Descriptive data is provided as frequencies and percentages. Depending upon normalcy, the quantitative values are given as mean ± standard deviation (SD) or median with interquartile range (Q1-Q3).

Ethical concerns: The study started after obtaining ethical permission from the Institutional Ethics Committee. Written informed consent was taken from each participant.

A total of 100 patients (M/F: 49/51) of DR-TB were recruited. The median age of patients was 24 years. Most patients (n=91) had pulmonary involvement. Extrapulmonary involvement was present in 16. The median duration of symptoms was 3 months. Baseline chest radiography was abnormal in 95% of the cases. Around one-third of the patients (n=34) had a history of intake of anti-tubercular therapy (ATT). The majority of the patients were RR-TB (n=90), and 10 patients were diagnosed with Pre-XDR TB. (Table 1)

Eighty-three patients were started on longer oral (LO) regimens and seventeen were started on short oral (SO) regimens following the NTEP guidelines. Out of 83 patients on the LO regimen, nine were lost to follow-up at 1 month. Among these, four patients died as informed by the caregivers at 3 months follow-up. One and two patients were subsequently lost to follow-up at 3 and 6 months respectively. Two patients on the SO regimen were shifted to LO at 3 months because of the emergence of new resistance to fluoroquinolone. Thus, 73 patients on LO regimens and 15 patients on the SO regimen could be followed up for therapeutic outcomes at 6 months. (Figure 1). The individual regimens received by the patients over the first 6 months are described below.

Long oral (LO) regimens:

For RR-TB:

Regimen A: Bdq, Lfx/Mfx, Lzd, Cfz, Cs

For Pre-XDR TB:

Regimen B: Bdq, Dlm, Lzd, Cfz, Cs for 6 months

Regimen C: Bdq, E, Lzd, Cfz, Cs for 6 months

The LO regimens started in due course due to intolerability to linezolid:

Regimen D: Bdq, Lfx/Mfx, Dlm, Cfz, Cs

Regimen E: Bdq, Lfx/Mfx, Z, Cfz, Cs

Regimen F: Bdq, Lfx/Mfx, E, Cfz, Cs

Short oral (SO) regimen: Bdq, Hh, Eto, Cfz, Lfx/Mfx, Z, E

3.1. Regimen-wise flowchart of participants over 6 months of follow-up

A total of 64 patients from regimen A could be followed up at 1 month. Because of culture sensitivity reports showing M. Tb resistance to fluoroquinolone, the latter was replaced by delamanid and ethambutol in nine and 1 patient respectively at 1 month. One patient had to be shifted from linezolid to delamanid because of intolerability. One patient was lost to follow-up at 3 months. Thus, 52 patients on regimen A, 16 patients on regimen B, and four patients on regimen C were followed up at 3 months. At 3 months, 7 patients in regimen A were shifted from linezolid to delamanid (Regimen D, n=4), pyrazinamide (Regimen E, n=2), or ethambutol (Regimen F, n=1) because of intolerability to Lzd. In one patient, the fluoroquinolone was replaced by delamanid because of new resistance to fluoroquinolone. Additionally, at 3 months, two patients from the SO regimen were shifted to regimen A (high-dose moxifloxacin-based LO regimen) because of new resistance to levofloxacin. One patient in regimen D and one in regimen E were lost to follow-up after 3 months. Thus, 46 patients in regimen A, 17 in regimen B, 4 in regimen C, 4 in regimen D, 1 in regimen E, 1 in regimen F, and 15 in the SO regimen could be followed up at 6 months. Figure 1 shows the pictorial representation of patients enrolled and followed up at various time intervals over 6 months.

3.2. Therapeutic outcomes over 6 months of follow-up (Figures)

3.2.1. Therapeutic outcomes with LO regimen

3.2.1.1. Microbiological and clinical improvement

Out of 73 patients of the LO regimen followed up at 6 months, 62 (84.9%) achieved microbiological improvement in the form of smear or culture conversion in at least one sample. Among these, 17 (23.3%) patients attained microbiological improvement as early as 3 months. Regimen-wise, 92.4% of patients in regimen A, 71.3% of patients in regimen B, and 75% of patients in regimen C attained microbiological improvement in at least one sample over 6 months of follow-up. All patients testing negative at 3 months (n=17) showed improvement in the second sample taken at a gap of more than seven days. Cumulatively, 41 out of 62 patients (66.1%) showed microbiological improvement in the 2^nd sample till the last follow-up. Reports were not available for the remaining 21. Significant clinical improvement at 6 months (≥ 50% improvement in symptoms) was reported by 69 (94.5%) patients.

3.2.1.2. Adverse events

Peripheral neuropathy (PN), skin pigmentation and anemia (fall in hemoglobin by > 2gm/dL from baseline) were the three common AEs, noticed in 41 (56.2%), 32(43.8%), and 26 (35.6%) patients respectively. Treatment modification due to AEs was required in 40 patients (54.8%). Specifically, nine (12.2%) patients, 22 (30.1%), and 18 (24.6%) patients had AEs that required change in the regimen at 1 month, 3month and 6 months respectively. Out of 41 patients developing PN, the regimen had to be modified for 34 (82.9%). Regimen wise, PN requiring treatment modification occurred in 49.2%, 30.4%, and 75% of patients in regimen A, regimen B, and regimen C respectively over 6 months of therapy. Among 26 patients developing anemia, a change in regimen was required in 3 (11.5%). The incidence of anemia increased over 6 months of therapy with 32.6% of patients in regimen A, 29.4% of patients in regimen B and 50% of patients in regimen C developing a fall in hemoglobin. Optic neuritis developed in two patients (one in regimen A and one in regimen B) and in both, the regimen was subsequently changed. No patient required treatment modification because of hyperpigmentation of the skin. (Table 2)

Among other AEs, thrombocytopenia (fall in platelet count by > 50% of baseline) occurred in 19 (26%) patients. Thrombocytopenia occurred in 17.6-28.6% of patients in regimen B and in 15.2-15.6% of patients in regimen A. One patient in regimen A required treatment modification due to thrombocytopenia. Significant hepatitis (>5 times elevation in liver enzymes compared to baseline) was noticed in 10 (13.7%) patients and was common in regimen B (17.6%) at 6 months. Nearly 3.8-4.7% of patients on regimen A developed significant hepatitis. Hyperuricemia was also common with regimen B (11.8-12.5%). While 4 patients had an increase in QTc to more than 450 msec at 6 months, no female patient had QTc prolongation of > 470 msec, and no patient had an increase in QTc to more than 500 msec. Three among these belonged to regimen A (6.5%) and one to regimen B (5.8%). The median increase in QTc and PR interval at 6 months were 15 msec and 6 msec respectively compared to baseline. Hypokalemia occurred in 23.3% of patients, was common at 1 month (Regimen A, 12.5% and regimen B, 14.3%) and decreased over 6 months of therapy. Four (5.5%) patients with normal TSH at baseline had TSH elevated to > 5 mIU/mL at 6 months. These patients belonged to regimen A.

3.2.2. Therapeutic outcomes with SO regimen

Out of 17 patients enrolled, cumulative microbiological improvement was noticed in 67.9% (n=11) at 6 months. Seven patients (41.2%) attained microbiological improvement as early as 3 months of therapy. Among the 11 patients, the second sample collected after 7 days was negative for mycobacterium in 6 (54.5%) and reports were not available for the remaining five patients. All except one reported significant (≥ 50%) clinical improvement at 6 months (93.3%). (Table 2)

Hyperuricemia(n=5), gastrointestinal symptoms (n=5), skin pigmentation (n=5) and hypokalemia (n=5) were the commonly observed AEs. The incidence of hyperuricemia increased with time to 26.6% at 6 months. (Table 2) Hypokalemia was noticed in 13.3-17.6% of individuals. These AEs, however, did not necessitate a change in the regimen. The AEs requiring treatment modification were noted in 5.8%, 11.8%, and 13.3% of patients at 1 month, 3 months, and 6 months respectively. These included three cases of peripheral neuropathy (5.8-13.3%) and a case of significant hepatitis. The QTc and PR intervals increased by a median value of 9 and 7 msec respectively.

3.3. Modifications in the LO regimens

Among 74 individuals in the LO regimens, treatment modification was required in 45 (60.8%). (Figure 2a) The major reason for the change in the regimen was intolerability (31, 42.5%). Both resistance and intolerability were the reasons for treatment modification in eight (10.9%). Cumulatively, intolerability contributed to modification of the initial regimen in 40 out of 45 cases (88.8%).

3.3.1. Treatment modification due to AEs

The commonest AE that prompted a change in regimen A was linezolid-related peripheral neuropathy (PN) which occurred in 26 (49.2%) patients. Anemia and optic neuritis were responsible for treatment modification in three patients (1.6-2.2%) and one patient (1.9%) respectively. Details are mentioned in Table 3. Linezolid-associated PN was the AE that prompted a change in the regimen in 5 (30.1%) and 3 (75%) patients on regimen B and regimen C respectively. One patient in regimen B developed optic neuritis which prompted a change in the regimen.

To manage the AEs, the dose of linezolid was reduced to 300 mg OD in 33 patients (45.2%). Among these, 21 patients required dose reduction of linezolid over 3 months, and the AE resolved in 12(57.1%) by 6 months. Despite dose reduction, sixteen patients (76.2%) showed microbiologic improvement at 6 months. Linezolid had to be stopped altogether in 13 (17.8%) patients over 6 months of therapy. In eight out of these 13, the drug was stopped as early as after 3 months of therapy. The replacements included delamanid in 5 cases, pyrazinamide in 2, and ethambutol in 1 case. Cumulatively, at 6 months of therapy, the drug was substituted by pyrazinamide, delamanid, and ethambutol in seven, five, and one cases respectively. (Table 3) In two patients, bedaquiline was extended beyond 6 months of therapy. In one patient cycloserine was stopped at 6 months due to agitation and anxiety and was replaced by pyrazinamide.

3.3.2. Treatment modification due to additional resistance

Among 73 patients on the LO regimen that could be followed at 6 months, the development of additional resistance to fluoroquinolone caused a change in regimen A in 13 cases (17.8%). The fluoroquinolone (levofloxacin) was replaced by delamanid and ethambutol in 10 patients and 1 patient respectively. (Figure 1) In the remaining two patients, levofloxacin was replaced by high-dose moxifloxacin. The latter being another fluoroquinolone, these two patients were still categorized under regimen A.

3.4. Modifications in the SO regimen

Among seventeen patients in the SO regimen, 6 (35.3%) required modification in the treatment. (Figure 2b) The major reason for a change in the regimen was intolerability (4, 26.7%). Two patients (11.8%) developed additional resistance to levofloxacin and were shifted to the long oral regimen (regimen A containing high-dose moxifloxacin) at 3 months.

PN related to high-dose isoniazid was the commonest AE (n=3) that mandated change in the SO regimen. To manage the AE, the dose of isoniazid had to be reduced to 300 mg in all three patients. (Table 3)

The present study provides data on the therapeutic performance of all-oral regimens approved by WHO for DR-TB, evidence on which is scarce globally and more so from the Indian settings. Importantly, the study comments on the reasons for modifications of the initial regimen, the AEs necessitating modification, steps taken to manage the AEs, and drugs selected as replacements. Around 85% of patients in LO regimens and 68% of patients in the SO regimen showed microbiological improvement in at least one sample over 6 months of therapy. Regimen-wise, the cumulative rates of microbiological improvement in one sample were 92.4%, 71.3%, and 75% in regimens A, B, and C respectively. Among patients achieving microbiologic improvement in one sample, 66% of patients in the LO and 55% of patients in the SO regimen had their 2^nd sample negative for M. Tb till the last follow-up. Four deaths were observed all within the first three months in patients on LO regimens.

Previously, the evidence of treatment success and reduction in mortality with WHO-approved all-oral longer and shorter regimens was largely built by the retrospective cohort studies of DR-TB patients in South Africa. [5,6] Recently, a pooled treatment success rate of 77-82% was shown with bedaquiline-based oral or injectable regimens. [7]

More than 60% and nearly a third of patients in LO and SO regimens respectively required treatment modification and intolerability alone was the reason for around 2/3^rd. Altogether, intolerability necessitated modification in the regimen in 55% of patients in the LO and 26.7% of patients in the SO regimen. The fact that the majority of AEs require treatment modification has been highlighted in other studies also. [8] With peripheral neuropathy, anemia, and optic neuritis as the main reasons, the linezolid dose had to be reduced in nearly 45% of patients and the drug had to be stopped altogether in close to 18% of patients over 6 months of therapy. These rates of linezolid discontinuation are many times higher than the rates reported globally (2-4%) and may suggest an ethnicity-specific intolerability to linezolid in Indian patients. [8,9]. Despite dose reduction in linezolid over the first 3 months, 76.2% of the patients showed microbiological improvement over 6 months. The findings emphasize investigating the reduced dose of linezolid in DR-TB regimes as has been shown successfully in a few recent studies such as the ZENIX trial and in an Indian study. [10,11]. Though regimen C containing ethambutol as the fifth drug had a smaller representation overall, the rates of PN were higher (75%) in these patients. Ethambutol has also been associated with peripheral neuropathy. [12,13]. Accordingly, vigilance is warranted for the risk of neurotoxicity in regimens combining ethambutol and linezolid. Though clofazimine-associated skin pigmentation was noted in a significant percentage (43.2%), no change in the regimen was required. Among other AEs, anemia occurred in nearly a third of patients on LO regimen with incidence increasing over 6 months and a quarter of patients developed thrombocytopenia. Hepatic toxicity occurred in nearly 14% of patients on LO regimen. Thrombocytopenia, hepatitis, and hyperuricemia were common with regimens containing bedaquiline and delamanid. In a recently conducted South Indian study on DR-TB, a higher rate of hepatic disturbances (47%), the majority being mild-moderate, was noticed with the four drug-based regimen containing bedaquiline, delamanid, linezolid, and clofazimine. [11]. Larger studies with regimens combining Dlm with Bdq are needed to validate these safety findings. Tolerability to bedaquiline was favorable in the present study and in no patient, the drug had to be discontinued because of AEs. Apart from AEs, the development of additional resistance to fluoroquinolone necessitated regimen modification in 18% of patients in the LO regimen and delamanid was the commonest replacement.

The patterns and frequency of AEs differed in the SO regimen. Skin pigmentation, hypokalemia, hyperuricemia, and gastrointestinal disturbances were the common AEs, each observed in close to one-third of patients. The regimen was however changed because of high-dose isoniazid-related peripheral neuropathy and hepatic toxicity.

Around 5.4 % of patients in the long oral regimen developed QTc prolongation of >450 msec. However, only one male patient had QTc increased to > 450 msec and no female patient had QTc > 470 msec. Thus, significant QTc prolongation occurred in only 1.4% of patients in LO and none in SO regimen. The frequency of AEs with bedaquiline-based regimens has differed across the studies. In a pooled analysis of bedaquiline-based oral and injectable regimens, peripheral neuropathy (13.9%), hepatotoxicity (12.6%), hematological disturbances (12.5%), and QTc prolongation (10.2%), were the common AEs. [7] These disparities in rates of AEs can be explained by a higher inter-study heterogeneity related to the selection of drugs, inclusion of varying ethnicities, and inconsistencies in the definitions or grades of adverse events. Most of the studies included in this meta-analysis originated from South Africa, China, and South Korea and the representation of Indian studies was meager.

Results of other fully oral regimens that are being explored with interest in patients of DR-TB are described in Supplementary Table 1. With a treatment success rate of 91%, myelosuppression, skin hyperpigmentation, and peripheral neuropathy were the commonest AEs, each noticed in around half of the patients on Bdq, Dlm, Lzd, and Cfz -based shorter regimen. Similar to the findings of the present study, a higher percentage of patients developing PN (45/69, 65.2%) required a reduction in dosage of Lzd and no patient developed QTc prolongation of > 500 msec. [11] Newer all-oral shorter regimens (Bdq, Lfx, Lzd, Cfz, Cs and Bdq, Lfx, Lzd, Dlm, Cfz) with a composition similar to the LO regimen are being tried in patients with RR- TB, and the initial results have been successful. [14]

Limitation: The present study is observational in design and does not reflect the findings of controlled settings. However, the study carries the advantage of monitoring the patients of DR-TB in real-world settings. The study enrolled patients of the North Indian belt and larger studies with adequate representation of different ethnicities are required to extrapolate the observations to global context. Improvement was ascertained primarily as microbiologic improvement in one sample and patients’ reported clinical improvement. However, 55-66% of patients achieving microbiological improvement showed similar results in the second sample and significant clinical improvement was observed in all. Patients with HIV coinfection were excluded. ECG was monitored only at baseline and at 6 months and not in the intervening period due to feasibility issues. The effects of drug regimens on pancreatic enzymes were not evaluated. The representation of the SO regimen and that of bedaquiline-delamanid-based LO regimen was meager. Such regimens need to be investigated in a larger sample of patients to generate regimen-specific therapeutic outcomes. Likewise, the long-term outcomes of Lzd replacement by Dlm, Z or E should be evaluated through extended monitoring.

Successful therapeutic outcomes were observed in patients of DR-TB with all-oral bedaquiline-based regimens. Extended follow-up is required to understand the long-term sustenance of therapeutic effect. More than half of the patients on longer-oral and a quarter of patients on short-oral regimens required treatment modification due to intolerability with peripheral neuropathy as the commonest concern. Additional adverse events for which monitoring is warranted include hepatic disturbances, anemia, hyperuricemia, and thrombocytopenia. Linezolid in reduced dose or the drug replacement with pyrazinamide or delamanid may be explored in a larger sample. Considering the high rates of intolerability with the approved regimens, the need remains high for newer drugs and regimens with improved safety profiles.

Ethics statement: This study was approved by the Institutional Ethics Committee and follows the Declaration of Helsinki.

Conflict of Interest: None

Funding: None

Acknowledgment: None

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Tables 1 to 3 are available in the Supplementary Files section

No competing interests reported.

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Clinical outcomes with all-oral regimens in patients of drug-resistant tuberculosis: A prospective study in a tertiary hospital in North India

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