Characteristics and contributing factors of adverse drug reactions: an analytical study of patients with tuberculosis receiving treatment under the National TB Program of India

2.1 Study design and settings

A descriptive observational cross-sectional study was conducted from 3^rd May 2021 to 30^th July 2021 in the Western state of India, Gujarat. The study was conducted through the district tB centre (DTC) and 32 tuberculosis units (TUs) in Gandhinagar and Surat districts (Gujarat state), with TB patients registered and managed. NTEP has been implemented in all districts of the state. Each district has a district TB center, which monitors the program for the entire district. The district is further divided into sub-districts i.e., TUs, at each block. Under the TUs, outlying peripheral (government and private) health facilities (PHI) provide programmatic management for TB patients.

2.2 Study population and sampling method

The assessment targeted a diverse profile of TB patients, such as drug-sensitive TB (DSTB), drug resistance TB (DRTB), pediatric TB, and extra-pulmonary TB. It included both public and private sector patients. The patients diagnosed with TB are reported on the online digital patient management portal Nikshay in the notification registers by the health facilities.¹⁵ The list of reported TB patients from 1^st July 2018 to 31^st December 2020 was extracted from Nikshay to ensure that the study population completed treatment based on the duration of the treatment regimen. A total of 20,668 patients were reported in the Nikshay portal from both districts during that period.

The sample size was calculated based on the formula of N=Z21−α/2P(1−P)/ε2, where N=sample size, Z21−α=confidence interval, P=estimated proportion, ε=desired precision/error, with estimated proportion of 50% of ADR occurrences. Based on sample size calculation, it was derived that over 534 TB patients had to be included in the study to have a confidence level of 98% and a desired error that is within ±5% of the measured/surveyed value. Additionally, the final sample size accounted for around a ~10% non-response rate, bringing the number of study participants to about 593. The eligible TB cases were listed with the inclusion and exclusion criteria below. Inclusion criteria: the TB patients reported through Nikshay, their current state PHI was within the selected geographical areas of Gujarat state, and they were given treatment. Exclusion criteria: TB patients who migrated or were untraceable or did not reside in the current PHI surveyed areas or whose relatives didn't provide consent were excluded from the study.

From each TU, patients were recruited randomly depending on their availability and willingness to participate. Simple random sampling was adopted to select TB cases within the selected geographic areas until the saturation of the sample size. However, a proportionate adjustment based on the type of cases, service facility, and site of disease was considered for the unified distribution across the study geography to ensure the collective representation of the study participants.

2.3 Data variables and data collection

A semi-structured interview followed by a semi-structured, pilot-tested ADR assessment questionnaire was used to collect the data in the vernacular language (Gujarati). A pretested and semi-structured questionnaire tool consisting of information regarding primary socio-demographics, medical history, history of addiction and comorbidity, and information about the grade and type of ADRs was administered by the trained researchers in the vernacular language through personal interviews by undertaking home visits. The researchers were trained to administer the questionnaire with a participatory approach and role play to prepare them to interview the study participants for the required information.

2.4 Study definition for adverse drug reactions

The World Health Organization (WHO) has defined adverse drug reactions (ADRs) as “A response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease, or the modification of physiological function”.¹⁶ The cornerstones of DSTB therapy continue to be a treatment plan with a minimum duration of six months and numerous first-line medicines (FLDs), such as isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S). Similar to this, NTEP offers streamlined regimens for several forms of DR-TB, including shorter oral bedaquiline-containing MDR/rifampicin resistant-TB regimens and longer oral M/XDR-TB (mono or extreme drug resistant) regimens generally ranging from six to nine months but can reach up to 20 months. The drug dosages are adjusted based on the age, weight, severity of the disease, site of the disease, and type of drug resistance/susceptibility towards ATTs.

2.5 Data analysis

Once the data collection was completed, data sets were scrutinized for completeness and validation by the different sets of the researchers. The study participants were contacted again if any data variables were found to be missing by the researchers who had collected the primary data. The patient data on various variables was tabulated, analyzed, and interpreted by proper statistical methods using IBM SPSS statistics software version 20 (RRID:SCR_019096). The chi-squared test was used to compare groups, while the chi-squared for the trend examined linear trends. Risk measures were determined using odds ratios (OR) and 95% confidence intervals (CI). Crude OR and 95% CI were calculated for the interpretation of univariate analysis, with the level of significance set at p<0.05. To identify the independent factors associated with ADRs, adjusted odds ratios (AOR) and 95% CI were calculated by bivariate logistic regression analysis.

3.1 Demographic profile of study participants

The mean age of study participants was 34.6±15.6 years, and the median age was 31 years, ranging from 1 to 85 years. The majority of study cases, 517 (87.2%), were in the age group of 15–60. There were 343 (57.8%) male patients and 250 (42.2 %) female patients. There were 99 (16.7%) illiterates, 52 (8.8%) graduates, and 133 (22.4%) daily laborers and 381 (64.2%) of the patients were married. The association between age categories, marital status, and education status and adverse drug reaction was not significant (p>0.05). However, among gender and occupation status, it was found to be significant (p<0.05) (Table 1).

3.2 Clinical profile of the study participants

The study participants were comprised of 147 (25%) extra-pulmonary TB (EPTB) patients and 446 (75%) pulmonary TB patients (PTB), 519 (87%) of whom had contracted the first episode of TB. The distribution of the type of cases as per national guidelines was 492 (83%) new cases and 69 (12%) previously treated cases on the drug-sensitive TB treatment regimen, while 32 (5%) cases were on the drug-resistant treatment regimen. A total of 66 (11%) TB patients were receiving treatment from private providers. The study reported that 268 (44.7%) had a history of addiction, with 91% addicted to tobacco (either smokeless or smoking) and 9% to alcohol. Among them, 41% had an addiction to tobacco and alcohol, while 1.2% had addictions to psychotic substances. Sixty-one (10%) reported the presence of at least one comorbidity, while the major contribution of comorbidity was diabetes (50%). The number of patients with a HIV co-infection was deficient in numbers to be included in a detailed analysis.

3.3 Adverse drug reactions among the study participants

During the study, it was observed that 172 (29%) patients experienced ADRs with at least one symptom. Out of those, 80% had mild symptoms, and 133 (77%) experienced them during the early (intensive) phase of the treatment initiation. The 18 (56%) drug-resistant TB patients on second-line ATTs reported ADR, 50% of whom reported moderate and severe ADRs. The association between ADR experience and drug susceptibility was significant (p value of 0.005; Chi-squared 12.193) and drug-resistant TB patients experience two times more ADRs than drug-sensitive TB patients (OR 2.049, CI: 1.47–2.86). The TB patients had experienced gastric disturbances, skin-related symptoms, peripheral nervous system symptoms, arthralgia, ophthalmic discomfort, and psychological disorders during ATT (Table 2).

3.4 Logistic regression on predictive independent variables

The study used a binomial logistic regression model to estimate the bivariate odds ratio and a 95% confidence interval to describe the association between predictor variables and the occurrence of ADRs. The study used the dataset's socio-demographic, clinical, and programmatic service delivery variables to develop the predictive model. The model showed that gender, drug susceptibility status, and history of addiction were statistically significant (p<0.05). The regression model showed that the Nagelkerke R2 value was 0.139 with a classification accuracy of 71% (Table 3).

Limitations

The present study recorded ADRs or adverse events from the history of patients that could lead to subjective variations and recall bias. The type and grade of ADRs were also recorded from the patient's perspective, limiting the researchers to identify the drug-specific symptom of ADRs. In the absence of patients' medical records, the study could not assess or record the nutritional status at the time of ATT, the severity of comorbidity, or confirm hospitalisation due to severe ADRs. This was one of the reasons that during the study, researchers had not considered the history of stoppage of the offending drug(s), alterations in the treatment regimen, or management received for the discomfort. The study excluded one TB patient who was non-traceable at the time of the data collection. The excluded TB patient could have provided additional information that support the results.