INTRODUCTION

The standard term for tuberculosis (TB) produced by organisms resistant to at least isoniazid and rifampicin, the two most effective anti-TB drugs, is multidrug-resistant TB (MDR-TB).[1] The two categories for MDR TB are either second-line injectable drugs or MDR/rifampicin resistance (RR) + fluoroquinolone resistance, according the guidelines for the programmatic management of drug-resistant tuberculosis. The first national anti-TB drug resistance study found that 6.19% of TB patients had MDR-TB (2.84% among new and 11.62% among previously treated [PT]), and 28% of TB patients were resistant to all forms of treatment (22% among new and 36.82% among PT).[2] Moreover, the main cause of RR-TB is isoniazid (H) resistance (16% overall, 11.6% in new cases, and 25% in PT). The usage of second-line antitubercular drugs, which are frequently required to treat MDR-TB, may be to blame for the rising incidence of resistance. Consequently, these drugs that need to be taken for a long time, are hazardous, and expensive.[2]

“A response which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function” is the definition of an adverse drug reaction (ADR) provided by the World Health Organization (WHO).[3] ADRs are increasing among MDR-TB patients in India.[4] Therefore, doctors should identify and treat ADR to second-line antitubercular therapy as soon as possible to avoid treatment failure. Better treatment outcomes and patient compliance are guaranteed by this approach. Although ADRs among MDR-TB patients have been reported in various parts of India, there is a lack of region-specific data from Meghalaya and the Northeastern states. National data on ADRs in MDR-TB patients often lack region-specific details, which may overlook local variations in ADR patterns due to differences in genetic, nutritional, and healthcare factors. In addition, limited pharmacovigilance awareness and underreporting hinder a clear understanding of the ADR burden and its impact on treatment adherence in this region. Identifying the profile and frequency of ADRs among MDRTB patients in Meghalaya is essential for timely management, improving treatment outcomes, and strengthening the local TB control program. Therefore, this study was undertaken to systematically evaluate the types, frequencies, and management of ADRs associated with MDR-TB therapy in patients attending a tertiary care center in Meghalaya.

MATERIAL AND METHODS Study design and setting

A prospective, observational study was conducted among MDR-TB patients admitted during the period of April 2018 toDecember 2018 in the District TB Center.

Study population

Patients diagnosed as MDR-TB and enrolled for treatment at the District TB Center.

Ethical considerations

The Institutional Ethics Committee permission was obtained.

Inclusion criteria

All registered MDR-TB cases were included

MDR-TB patients with suspected ADRs

Patients aged 18 years and above.

Exclusion criteria

TB cases other than MDR were excluded from the study

Pregnant women

HIV-positive individuals

Patients having concurrent major cardiac, renal, hepatic, and/or psychiatric illness.

Data collection technique

Following approval from the Institutional Ethics Committee, a prospective observational study was conducted at the District TB Hospital from April 2018 to December 2018. All consenting adult patients diagnosed with MDR-TB and initiated on treatment during the study period were included in the study. Patients with incomplete treatment records or those unwilling to participate were excluded from the study. Baseline demographic and clinical details, including age, gender, weight, and comorbidities, were collected using a pre-designed structured pro forma at the time of treatment initiation. Patients were followed prospectively during their hospital stay and subsequent outpatient visits, with monthly monitoring for 6 months for any suspected ADRs.

ADR data were captured using an ADR reporting form, documenting details on the onset of the reaction, suspected drug, dosage, frequency, management strategies, and treatment outcomes. Active data collection techniques included direct patient interviews, clinical examination, review of patient treatment charts, and laboratory investigations (if required) to confirm suspected ADRs.

The Naranjo ADR Probability Scale was applied to assess the causality of reported ADRs, categorizing them as definite, probable, possible, or doubtful. The Modified Hartwig and Siegel severity scale was used to grade the severity of each ADR. ADRs were further analyzed to determine whether they resulted in dose modification, temporary interruption, or permanent discontinuation of the offending drug. Data were entered and analyzed using Microsoft Excel with descriptive statistics presented as frequencies and percentages.

Statistical analysis

Data were analyzed using Microsoft Excel and expressed using descriptive statistics. Categorical variables were presented as frequencies and percentages.

RESULTS

The study included 120 participants over its duration. Figure 1 depicts the patient distribution by gender throughout the course of the study. The majority of patients (62%) were male, with females accounting for 38%. The age distribution indicated in Table 1 shows that most patients (66%) were between the ages of 21 and 40 years, with the other patients aged between 41 and 60 years (28%).

Figure 1: Gender distribution of patients.

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Table 1: Age wise distribution of patients.

Age (in years) Frequency (n) Percentage 0–20 - - 21–40 79 66 41–60 34 28 >60 7 6

In the present study, 54 ADRs were documented. Females had a higher incidence (57%) than males (43%) [Figure 2]. The majority of ADRs (33%) were gastrointestinal (nausea and vomiting). This was followed by diarrhea (6%), then psychosis (6%). In 7 of 18 instances (13.33%), isoniazid was suspected to be the cause of gastrointestinal problems. The medicine was withdrawn in three patients after they complained of severe nausea and vomiting on many occasions. The distribution and characteristics of other adverse medication events are shown in Table 2.

Figure 2: Gender distribution of patients with adverse drug reaction. ADR: Adverse drug reactions.

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Table 2: Incidence and characteristic of ADRs (n=54).

ADRs Incidence (%) Days of treatment at presentation (median days) Change in regimen due to ADR (n) Suspected drug Permanent discontinuation of drug due to ADR (%) Gastrointestinal (nausea and vomiting) 18 (33) 90 3 7 (isoniazid)
4 (ethambutol)
4 (pyrazinamide)
3 (ethionamide) 3 Diarrhea 6 (11) 30 0 2 (ethionamide)
3 (pyrazinamide)
1 (ethambutol) 0 Hearing loss 6 (11) 70 2 6 (kanamycin) 2 Weakness 4 (7) 80 0 2 (kanamycin)
1 (isoniazid)
1 (rifampicin) 0 Psychotic symptoms 6 (11) 60 2 5 (cycloserine)
1(ethambutol) 2 Corrected QT interval 2 (3.7) 90 1 1 (clofazimine)
1 (linezolid) 1 Altered consciousness 2 (3.7) 68 1 2 (ethionamide) 1 Headache 5 (9.2) 60–90 days 0 1 (levofloxacin)
4 (cycloserine) 0 Jaundice 1 (1.8) 30 0 1 (pyrazinamide) 0 Weight gain 2 (3.7) 64 0 2 (kanamycin) 0 Peripheral Neuropathy (1.8) 84 0 1 (isoniazid) 0 Insomnia 1 (1.8) 36 0 1 (levofloxacin) 0

The causality assessment of the ADRs reported in the study was done using the Naranjo ADR Probability Scale. The “possible” category accounted for the majority of ADRs (65%), while the “probable category” comprised 35%. The causality assessment for the ADRs is shown in Table 3. The majority of ADRs reported throughout the study were found to be mild, or level 1 (68.5%), followed by moderate, or level 3 (18.51%). Severe ADRs accounted for 1.8% (category 6). The Modified Hartwig and Siegel scale was used to determine the severity of ADRs, as shown in Table 4.

Table 3: Causality assessment of adverse drug reactions using Naranjo adverse drug reaction probability scale.

ADR (54) Certain Probable Possible Gastrointestinal (nausea and vomiting) - 3 15 Diarrhea - - 6 Hearing loss - 6 - Weakness - - 4 Psychosis - 4 2 QT interval prolongation - 1 1 Altered consciousness - - 2 Headache - 1 4 Jaundice - 1 - Weight gain - 1 1 Peripheral neuropathy - 1 - Insomnia - 1 - Total (%) 19 (35) 35 (65)

Table 4: Severity assessment of adverse drug reactions.

ADR (54) Mild (level 1) Mild (level 2) Moderate (level 3) Moderate (level 4) Severe (level 5) Severe (level 6) Severe (level 7) Gastrointestinal (nausea and vomiting) 16 2 - Diarrhea 6 - Hearing loss 3 2 - 1 Weakness 4 - Psychosis 4 - 2 - QT interval prolongation - 2 - Altered consciousness 1 1 - Headache 4 1 - Jaundice - 1 - Weight gain 2 - - Peripheral neuropathy 1 - - Insomnia - 1 - Total (%) 37 (68.5) 4 (7.4) 10 (18.51) 2 (3.7) 1 (1.8) DISCUSSION

There was a male preponderance among the 120 MDRTB patients included in the study, with 62% of them being male and 38% being female. This is explained by differences in male and female immunological sensitivity to certain diseases, as well as social and cultural factors that raise the risk of coming into contact with infectious cases.[5] Ahmed et al. and Fatima et al. reported similar outcomes.[6,7] The age range of the majority of patients (66%) is regarded as economically productive, spanning from 21 to 40 year. Due to financial responsibilities, exposure to resistant strains in the environment, and an increased risk of addictions such as alcoholism, smoking, and psychological stress, all of which lower immunity, this age group is particularly vulnerable.[8] The study conclusions were at odds with those of Dela et al. and Fatima et al., who observed similar outcomes.[7,9] Both the kidney and the liver capacity to eliminate pharmaceuticals from the body decreases with age. The liver capacity to metabolize several medications also decreases. Malnutrition and dehydration are two conditions that often worsen these age-related problems and become increasingly common as people age.[9]

The present study included 21 participants who reported a total of 54 ADRs, indicating that each patient experienced several ADRs. A real-time spontaneous reporting technique was employed by physicians to record ADRs in research conducted by Shinde et al.[10] However, the present study only included patients who had reported ADRs and were hospitalized with MDR-TB. There might have been cases of underreporting ADRs as a result. The most frequent ADR was gastrointestinal discomfort (33%), which was followed by psychosis (11%), headaches (11%), and ototoxicity (11%). According to Hire et al., hepatotoxicity (3.6%), psychosis (4.5%), and G.I.T. symptoms (30%) were the most common ADRs.[11] According to Wu et al., gastrointestinal problems (32.1%), ototoxicity (14.6%), psychosis (13.2%), and arthralgia (8.1%) were the four most common ADRs.[12] The most frequent ADRs in the GI system were nausea and vomiting (33%), which had mild-to-moderate intensity and began 1–3 months after treatment. In seven of the 18 cases (13.33%), isoniazid was the suspected drug. Three patients had their medications stopped due to frequent complaints of acute nausea and vomiting. The majority of patients with diarrhea (11%), who were suspected of taking medications, took pyrazinamide (3), ethionamide (2), and ethambutol (1). On the severity scale, the suspected ADR was classified as “mild” (level 1) and patients received symptom-focused care.

Psychiatric symptoms (11%), including hallucinations, anxiety, depression, euphoria, and behavioral issues, were also reported. Cycloserine was the suspected drug in most patients who experienced psychiatric adverse drug responses. The medication was discontinued in two patients who had significant (level 4) ADR. Reduced gamma-aminobutyric acid synthesis in the central nervous system (CNS) due to glutamic decarboxylase inhibition is most likely the cause of cycloserine-associated neurotoxicity.[13] When the medicine was stopped, the majority of patients showed a quick recovery of psychological state and showed no recurrence of symptoms. In this study, psychological concerns surfaced during the first 2 months of treatment. When used with ethambutol, supratherapeutic dosages of cycloserine also seem to raise the risk of CNS damage.[14] Psychosocial variables, in addition to drug toxicity, play a role in psychological issues during MDR-TB treatment and, as a result, in patients’ compliance with treatment plans.[15] In MDR-TB patients, QT interval prolongation (3.7%) was also noted. The most often suspected drugs among study participants with QT prolongation were clofazimine and linezolid. The drugs were causing moderate level 3 QT prolongation in two individuals, and their further use was stopped. Possible pharmacological interactions with other drugs that increase corrected QT interval prolonging effects may be associated with an increased risk of ADRs with these drugs.[16] One of the most reported irreversible ADRs in MDR patients is ototoxicity. Six (11%) participants in the study experienced ototoxicity, with kanamycin being the offending medication. After receiving therapy for 2–3 months, the patients reported mild-to-severe hearing loss. The two patients in the present study had ADRs that were categorized as “severe” (level 6 on the severity scale). Consequently, those people had to stop taking their medication. The WHO medication class has removed capreomycin and kanamycin due to their subpar therapeutic outcomes. According to Lan et al., ADRs were associated with kanamycin, capreomycin, and amikacin in 7.5%, 8.2%, and 10.2% of cases, respectively.[17] Capreomycin was more nephrotoxic than kanamycin or amikacin and was also more likely to produce ototoxicity.[17] One patient experienced peripheral neuropathy, jaundice, and insomnia during the study; none of these side events necessitated altering the prescribed course of care. One to three months following the start of therapy, each of these ADRs was recorded. The Naranjo ADR Probability Scale was used to determine the causality assessment of ADRs. It was revealed that 65% of the ADRs were “possible” and 35% were “probable.” ADRs were suspected in 35/54 cases (65%). The remaining ADRs were assessed as probable. Dela et al. discovered that 4.79% were “certain,” 13.69% were “probable,” and 81.95% of ADRs were “possible.”[9] In this study, severity was determined using the Modified Hartwig and Siegel scale. The most reported ADR was “mild-level 1” (68.5%), followed by “moderate-level 3” (18.5%). About 1.8% of reported ADRs were classified as “severe-level 6.” Dela et al. found that 77.3% of ADRs were mild-to-moderate, while 22.7% were severe.[9] A study done by Hoa et al. showed that mild-to-moderate ADRs were 58% and those that were severe occurred in 17.73% of cases.[18]

ADRs among MDR-TB patients were most common in the first 3 months after starting MDR-TB treatment. These were followed by 29.5% in the 4–6 month period and 9.1% in the 7–9 month period. Similarly, most ADRs in a study led by Avong et al. developed after 1–2 months of medication and disappeared after 1 month of therapy.[19] The majority of adverse reactions happened in the 2nd and 4th months after beginning MDR-TB medication, according to Isaakidis et al.[20] Nine out of the twenty-one participants in this study (42.8%) had to stop taking the drug in question and switch their medication. In comparison, 56.3% (45/80) of patients experienced ADRs in a study conducted by Baghaei et al. Of these patients, 21.2% found it necessary todiscontinue the medication.[21]

Limitations

There is a chance of reporting bias because some ADRs, such as nausea, vomiting, and numbness, were reported by patients in an arbitrary manner. The fact that the few ADRs were documented based on clinical evaluations as opposed to laboratory standards was an additional drawback. They were therefore highly arbitrary. Determining whether an effect is related to the TB medication or the disease itself presents another challenge when documenting ADRs.

CONCLUSION

This study highlights the high rate of ADRs in MDR-TB treatment, impacting adherence and outcomes. Physicians should monitor patients closely for ADRs and manage them promptly to prevent treatment interruptions. For policymakers, the findings stress the need to strengthen ADR reporting and management within TB programs to improve MDR-TB treatment success in the region.