Adverse Drug Reactions with First-Line and Second-Line Drugs in Treatment of Tuberculosis

Introduction

India features among the 30 high-tuberculosis (TB) burden countries and has accounted for an estimated one-quarter (27%) of all TB cases worldwide.¹ Drug-susceptible TB (DS-TB) is treated with regimens containing multiple first-line drugs (FLDs') such as isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E), whereas second-line drugs (SLDs') and few FLDs' are reserved for treatment of drug-resistant TB (DR-TB). Good bacteriological diagnosis and compliance to treatment remains two main pillars of successful treatment of TB. An adverse drug reaction (ADR) has been defined as “a response to a drug which is noxious and unintended and which occurs at doses normally used in human for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.”² Patients may encounter with a variety of ADRs' when managed with anti-TB drugs. ADRs cause significant morbidity and even sometimes mortality if not detected early.^3,4,5 Major concerns exist regarding treatment of DR-TB patients, especially with SLDs having lower efficacy, costly and more toxic as compared to FLDs. Most of ADRs are mild or minor and can be managed without discontinuation of treatment. Few ADRs can be severe or major causing life-threatening experience leading to discontinuation or modification of treatment that may require hospitalization and even mortality if unrecognized and untreated promptly. Various factors, such as timing of occurrence of ADR, pattern of illness, results of laboratory tests, rechalle.g., with type, dosing or timing of drugs administration, patient age, nutritional status, the presence of preexisting diseases, or dysfunctions (such as impaired liver function, impaired kidney function, human immunodeficiency virus (HIV) coinfection, and alcoholism), might be attributed to causality of ADRs.⁶ Therefore, continued surveillance of ADRs is essential particularly in DR-TB cases where early detection and timely management of ADRs might determine successful outcome. This review aims to highlight the estimated burden and management strategies of various ADRs associated with anti-TB drugs among patients undergoing treatment of TB.

Epidemiology of Adverse Drug Reactions with First-Line Anti-TB Drugs

The data on global prevalence of ADRs with FLDs is scarce. The global prevalence of ADRs is variable ranging from 8 to 85%.^{3,7,8,9,10,11,12,13} The reasons for the difference in the prevalence of ADRs might be related to several possible factors, such as differences in definitions of ADRs terminologies, as adopted by physicians, whether the ADRs were reported by patient (subjective) or detected by clinician (objective) on the basis of clinical evidence along with feasibility of monitoring with serial laboratory investigations, whether all or only the major ADRs were studied, associated comorbidities, such as diabetes and HIV coinfection and variations in the use of specific anti-TB drugs including dosage, and also pharmacological interactions with other group of drugs comprising antiretroviral therapy (ART), oral hypoglycemic agents, and also ancillary medications used for management of ADRs. A study conducted in Nigeria observed that around 14 and 13% incidences of ADRs at 6 and 8 months, respectively. among patients receiving directly observed treatment and short-course (DOTS).¹⁰ Brazilian National Ministry of Health reported the incidence of minor or mild ADRs in patients treated with the former FLDs to range from 5 to 20%.¹¹ It was also observed that major or severe ADRs' were less common (occurring in approximately 2% of the cases, reaching 8% in specialized clinics) and led to the discontinuation or alteration of the treatment. There were no difference in incidence of ADRs among patients having intermittent and daily intake of anti-TB drugs.¹⁴ ADRs were more prevalent in intensive phase than continuation phase. The overall prevalence of ADRs with FLDs is estimated to vary from 2.3 to 17% in various Indian studies.^7,15,16,17 A study conducted by Mehrotra observed that the prevalence of ADRs in the initial intensive phase was 17.39%.¹⁵ Another study conducted at a tertiary institute in Calcutta observed that the overall toxicity was found in 35% cases in the daily regimen group, whereas it was found to be 27.9% in the intermittent regimen group.¹⁸ Data regarding prevalence of ADRs are still scarce and further surveys are required from different geographical areas of India in near future.

Epidemiology of ADRs Treated with Second-Line Anti-TB Drugs

The management of multidrug resistant (MDR)-TB patients has been considered to be complicated and challenging because of prolonged duration of 24 to 27 months of treatment and high-toxicity profile of SLDs. The prevalence of ADRs observed in various studies conducted worldwide ranged from 69 to 96%.^{19,20,21,22,23} Reasons for the difference in the prevalence of ADRs are almost similar to that of FLDs except the fact that regimens for DR-TB contains repurposed drugs like linezolid (Lzd) and clofazimine (Cfz), as well as newer drugs such as bedaquiline (Bdq) and delamanid (Dlm). The observed frequency of specific gastrointestinal (GI) ADRs (0.5–100%) followed by ototoxicity (12–70%) among patients receiving SLDs. Tinnitus has been reported in 5 to 45% of patients whereas deafness in 6.7 to 33% patients. Ototoxicity is predominantly associated with the use of injectable aminoglycosides such as kanamycin (Km). There is possibility of additive effects of interaction with other concomitant and potentially ototoxic drugs that were used in the regimen such as ofloxacin (Ofx) and cycloserine (Cs). This warrants further investigation to uncover the possibility of these interactive effects. SLDs have reported to cause severe ADRs that have led to interruption of treatment in 19 to 60% of MDR-TB patients.^{19,20,21,22,23} The estimated high prevalence was due to early identification and aggressive management strategies adopted by national health programs. A study from Iran reported deafness and headache/psychosis occurring due to injectable Km and Cs, respectively, as major ADRs that required frequent discontinuation and/or substitution.²³ MDR-TB patients should be managed aggressively for ADRs during therapy, especially for ototoxicity and psychiatric disorders. Very few have specifically reported frequency of ADRs in India.^{19,24,25,26,27,28} A study conducted in Tamil Nadu reported ADRs associated with standardized treatment in 86.8% patients.²⁵ Severe ADRs' requiring either a reduction of dosage or termination of the offending drug(s), such as ethionamide (Eto), Ofx, Km, and Cs were observed in 58% patients. Higher incidence of ADRs associated with SLDs has been reported in HIV patients with MDR-TB coinfection. A study conducted in Mumbai among 67 HIV and MDR-TB coinfected patients treated with anti-TB treatment, as well as ART, and reported that ADRs were more frequent in this cohort with 71, 63, and 40% of patients experiencing one or more mild, moderate, or severe ADRs, respectively.²⁶ ADRs, such as GI disturbances (45%), peripheral neuropathy (38%), hypothyroidism (32%), psychiatric symptoms (29%), and hypokalemia (23%) were reported more frequently among this cohort. Eleven patients required hospitalization and permanent discontinuation of one or more offending drugs that were observed in 40% patients. No ADRs led to indefinite suspension of an entire MDR-TB or ART regimen. A study reported 46.9% of 98 MDR-TB patients experiencing at least one ADRs.²⁸ ADRs observed most frequently were nausea/vomiting in 24 (24.5%) patients, hearing disturbances in 12 (12.3%) patients, dizziness/vertigo in 10 (10.2%) patients, and arthralgia in 9 (9.2%) patients. Seventeen (17.4%) patients had major ADRs requiring change or stoppage of drugs that included ototoxicity (6.1%), headache and psychosis (4.1%), GI intolerance and hypothyroidism (3.1%), as well as arthralgia and hepatitis (4.1%).²⁸ Agents responsible for these ADRs were Km (ototoxicity), Cs (headache/psychosis), Eto (GI tolerance/hypothyroidism), and Z (arthralgia/hepatitis). However, no mortality was observed due to occurrence of ADRs. Further studies are required for prevalence of ADRs' in near future.

Specific Adverse Drug Reactions Associated with Anti-TB Drugs

Immunological and Hematological Adverse Drug Reactions

R has been associated with immune mediated thrombocytopenic purpura and hemolytic anemia, especially with intermittent dosing. In a Brazilian study, R-induced thrombocytopenia, leukopenia, eosinophilia, hemolytic anemia, agranulocytosis, vasculitis, acute interstitial nephritis, and septic shock occurred in 0.1% of the patients.^33,54 However, a few Asian studies reported allergic reactions with FLDs to be between 2.02 and 2.35% and hematological ADRs to be 0.1 to 0.7%. Author in his work on hematological abnormalities during therapy found that thrombocytopenia, characterized by a rapid lowering of the platelet count in sensitive individuals was observed. Generally, the most common offending agent for the causation of thrombocytopenia secondary to anti-TB drug is R.^54,55 Isolated case reports showing thrombocytopenia following administration of Z, H, and E are found in literature and are attributed to an immunological phenomenon.^54,55,56,57 S is very rarely implicated as a cause of thrombocytopenia. Lzd has reported to be associated with hematological ADRs most common being thrombocytopenia with reported incidence as high as 11.8%.⁵⁸ Other ADRs like pancytopenia and myelosuppression are less common as compared to thrombocytopenia. These hematological ADRs are dose-dependent and usually reversible with clinical management.

Arthralgia

Z and E are two anti-TB drugs that have been reported to induce hyperuricemia in nongouty patients leading to arthralgia.⁵⁹ The metabolite pyrazinoic acid is likely responsible for the hyperuricemic effect. The mechanism is related to pyrazinoic acid, the principal metabolite of Z getting further oxidized by xanthine oxidase that inhibits the renal tubular secretion of uric acid. Hyperuricemia has been reported in 43 to 100% of patients treated with Z (alone or in combination).⁶⁰ Gouty attacks have also been associated with patients taking Z and E, as this combination can also cause hyperuricemia by decreasing renal uric acid clearance, but it does so less consistently and to a lesser degree than Z alone. Arthralgia has been reported with FQs particularly Lfx and Bdq containing regimens for DR-TB.^61,62

Renal Toxicity

Aminoglycosides produce renal toxic effects due to their accumulation in the renal tubules. Such effects are more common in elderly individuals and in patients with a history of kidney disease. Prolonged use of aminoglycosides, hepatotoxicity, dehydration, hypotension, and concurrent use of nephrotoxic drugs are other risk factors for renal toxicity. The risk of nephrotoxicity is less and range around 2% while using S.^63,64 Injectable drugs such as Km and Am, as well as Cm are more nephrotoxic as compared to S making treatment for DR-TB cases challenging with reported incidence of 1.2 to 6.7%.⁶⁵ E, Z, and Cs have been reported to cause renal toxicity. Newer drugs such as Bdq and Dlm can be used safely in DR-TB patients with renal failure.

Cutaneous Adverse Drug Reactions (CADRs)

Z has been described to cause various skin reactions like maculopapular rash, erythema multiforme, exfoliative dermatitis, drug rash, and eosinophilia with systemic symptoms (DRESS) syndrome. Among the FLDs, Z is the commonest cause of CADRs (2.38%), followed by S (1.45%), E (1.44%), R (1.23%), and Z (0.98%).⁶⁶ It is not uncommon for exfoliative dermatitis to occur with more than one of the four above drugs. The incidence of E-induced rash is found to be 0.5%. The author (R.P.) reported a rare occurrence of exfoliative dermatitis secondary to E and Z in an 18-year-old female.⁶⁷ Patients receiving H can develop antinuclear antibodies during the use of the drug. Less than 1% develops systemic lupus erythematosus (SLE), the incidence of which is the same in both genders. H administration can also worsen preexisting lupus. Rash has also been reported with any SLDs including newer ones Bdq and Dlm.⁶⁸

Cardiotoxicity (QTc Prolongation)

QTc prolongation on electrocardiogram (ECG) has been reported with FQs particularly moxifloxacin (Mfx), macrolides such as clarithromycin (Clr), Cfz, Bdq, and Dlm.⁶⁹ Risk factors for QTc prolongation include elderly, female sex, underlying cardiac disorder including congenital and acquired, electrolyte imbalance, and concurrent use of ancillary medications. A systematic search showed that Bdq is a relatively well-tolerated drug, as its discontinuation occurred in only 3.4 and 0.6% of patients due to ADRs' and QTc prolongation, respectively.⁶⁹

Miscellaneous Adverse Drug Reactions

Few case reports on H and Eto/Pto induced gynecomastia and alopecia among patients treated with anti-TB therapy.⁷⁰ A rare occurrence of anaphylactic shock due to S was also reported.⁷¹ Metallic taste has been reported with Eto/Pto and FQs.^33,43 Lactic acidosis has been associated with Lzd.^33,43

Management of Adverse Drug Reactions

Management of ADRs associated with anti-TB drugs is considered to be an essential component in order to achieve adequate adherence leading to favorable outcome particularly for DR-TB patients treated with toxic SLDs. Principles of pharmacovigilance have been adopted by the National TB Control Programmes all over the world. Pharmacovigilance is defined by the World Health Organization (WHO) as the “science and activities relating to the detection, assessment, understanding, and prevention of ADRs or any other drug-related problem.”⁷² The objective is to improve patient care by assessing both risk and benefit received from the drug. Routine surveillance of ADRs according to a framed protocol is an integral part of the National Programmes which should be performed by symptom-based reporting followed by laboratory investigations at baseline and as when clinically indicated. Occult ADRs' should be detected timely by laboratory investigations in order to prevent unrecognized serious effects. Monitoring should be frequent and more intense, particularly in high-risk groups, such as elderly, HIV or hepatitis coinfection, alcoholism, drug addiction, anemia, any preexisting illnesses, diabetes mellitus, hypoalbuminemia, malnutrition, chronic kidney disease, chronic liver disease, disseminated involvement, family history of frequent ADRs' or atopy/alle.g., and use of ancillary medications, and ART or medications for treating opportunistic infections with high probability of drug interactions. A grading system has been devised to assess severity of all types of ADRs' in order to maintain accuracy and consistency in surveillance.⁷³ This system includes five grades as follows: (1) grade 1: mild symptoms requiring only observation and no intervention; (2) grade 2: moderate symptoms requiring medical intervention such as ancillary drugs; (3) grade 3: severe symptoms with inability to carry social or functional activities requiring medical intervention or even hospitalization; (4) grade 4: life-threatening symptoms with inability to perform basic health care requiring medical intervention or hospitalization in order to prevent permanent impairment, disability or deaths; and (5) grade 5: mortality associated with ADR(s). Concept of active TB drug-safety monitoring and management (aDSM) has been introduced by WHO to provide active surveillance for detection of major or severe ADRs associated with novel DR-TB regimens and newer drugs by systematic clinical and laboratory assessment.^74,75 Symptoms-based approach to management of minor and major ADRs to FLDs are tabulated in ►Tables 1-3. ADRs of second line anti-TB drugs is tabulated in ►Table 4 and management strategy of common ADRs are tabulated in ►Table 5.

Management of Adverse Drug Reactions in TB and HIV Coinfection

HIV patients experience more frequent ADRs to both anti-TB and other non-TB medications for other opportunistic infections, and the risk of ADRs enhances with the degree of immunosuppression.^20,21,26 Identifying one or more offending drugs responsible for ADRs in patients receiving concomitant therapy for DR-TB and HIV is very challenging. Many of the medications used to treat coinfection have overlapping or additive ADRs, as mentioned in ►Table 6.⁷⁵ The typical strategy of stopping all medications and rechallenging them one by one is not possible in these patients, as the risk of emergence of resistance, especially for ART, is very high. It should be noted that information regarding the frequency of ADRs is relatively scarce. Most of drugs have to be included in the regimens outweighing the benefit over risk despite of awareness regarding high probability of overlapping ADRs. If two drugs with overlapping toxicities are considered to be essential for therapy, intense monitoring of ADRs is to be considered rather than disallowing a certain combination. The treating physician, whether working in public or private sector, must notify all diagnosed cases to concerned DOTS center and can refer for further management.

Conclusion

The treatment of TB can cause a variety of ADRs. ADRs of varying severity are common during treatment of DS-TB and DR-TB, particularly in the intensive phase of therapy. Some ADRs become more prevalent in DR-TB patients coinfected with HIV. Most ADRs can be successfully managed on an outpatient basis through a community-based treatment program, even in a resource-limited setting. Concerns about severe ADRs in the management of DR-TB patients are justified; however, they should not cause delays in the urgently needed rapid scale up of SLDs. ADRs can be detected by clinical evidence in resource-limited settings. DR-TB can be cured successfully with appropriate combination of drugs if ADRs associated with them can be managed aggressively and timely. Newer and less-toxic drugs are needed to treat DR-TB patients over large scale. Accurate diagnoses and knowle.g., of the pharmacological properties of the drugs involved will allow professionals to tailor their approach to each individual case in near future.