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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 4  |  Page : 463-468

Incidence of adverse drug events among patients on second line anti-tuberculosis regimen in the littoral region of cameroon


1 Department of Microbiology and Parasitology, Faculty of Science, University of Buea, Buea; Tuberculosis Reference Laboratory, Regional Delegation for Public Health, Douala, Cameroon
2 Department of Microbiology and Parasitology, Faculty of Science, University of Buea, Buea, Cameroon
3 Department of Medical Laboratory Science, Faculty of Health Sciences, University of Buea, Buea, Cameroon
4 Littoral Regional Technical Group for the Control of Tuberculosis, Regional Delegation for Public Health, Douala, Cameroon
5 The Biotechnology Centre, University of Yaounde, Yaoundé, Cameroon

Date of Submission14-Aug-2021
Date of Decision18-Sep-2021
Date of Acceptance18-Oct-2021
Date of Web Publication14-Dec-2021

Correspondence Address:
Henry D Meriki
Department of Microbiology and Parasitology, Faculty of Science, University of Buea, Box 63, Buea
Cameroon
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_160_21

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  Abstract 


Background: An adverse drug event (ADE) is an injury resulting from medical intervention associated with a drug. This study assesses the incidence of ADEs among participants on second-line drugs for tuberculosis (TB) in Cameroon. Methods: This was a longitudinal observational study including 65 participants and carried out from January 2017 to December 2017. Markers of ADEs were obtained from creatinine, transaminase audiogram, and clinical data. Multivariate analysis was used to determine the association between predictors and ADEs. Results: Forty-eight (73.8%) of the 65 participants developed 72 ADEs. Fifty-four (75%), 11 (15.3%), and 7 (9.7%) of the 72 ADEs were classified as Grades 1, 2, and 3, respectively. Gastrointestinal disorders were most common (35 [46.6%]) followed by auditory injuries (16 [22.2%]), hepatotoxicity (11 [15.3%]), neurological disorders (6 [8.3%]), and kidney disorders (4 [5.6%]). The follow-up duration of this study was 11,250-person day (PDY). The incidence rate for ADEs was 4.3/1000 PDY and that for gastrointestinal disorders, auditory injuries, hepatotoxicity, neurological disorders, and kidney disorders was 3.1, 1.4, 1.0, 0.5, and 0.2 (/1000PDY), respectively. Kanamycin (65 [90.3%]), isoniazid (4 [5.6%]), and ethambutol (3 [4.2%]) were incriminated with ADEs. Most (29 [60.4%]) of the ADEs occurred during the first 2 months of drug initiation. There was an association between poor treatment outcome and ADEs (P = 0.04, odds ratio = 1.20, 95% confidence of interval = 0.21–6.80]. Conclusions: The incidence of ADEs is associated with several factors and most of them occurred during the intensive phase of treatment. Kanamycin was the most associated drug linked to ADEs requiring its replacement with a less toxic one.

Keywords: Adverse drug events, kanamycin, rifampicin-resistant tuberculosis


How to cite this article:
Mbuh TP, Meriki HD, Thumamo Pokam BD, Adeline W, Enoka F, Ghislain T, Mbacham WF, Ane-Anyangwe I. Incidence of adverse drug events among patients on second line anti-tuberculosis regimen in the littoral region of cameroon. Int J Mycobacteriol 2021;10:463-8

How to cite this URL:
Mbuh TP, Meriki HD, Thumamo Pokam BD, Adeline W, Enoka F, Ghislain T, Mbacham WF, Ane-Anyangwe I. Incidence of adverse drug events among patients on second line anti-tuberculosis regimen in the littoral region of cameroon. Int J Mycobacteriol [serial online] 2021 [cited 2022 Jan 25];10:463-8. Available from: https://www.ijmyco.org/text.asp?2021/10/4/463/332345




  Introduction Top


Tuberculosis (TB) is the leading reason behind morbidity and mortality among people living with human immunodeficiency virus (HIV), particularly in developing countries and Cameroon in particular.[1] The emergence of multidrug-resistant TB (MDR-TB) may be a major global concern, especially because it challenges patient survival and public health. The World Health Organization defines MDR-TB as strains of Mycobacterium that are resistant to isoniazid and rifampicin, with or without resistance to other first-line drugs. The global TB report of 2020 indicates that 137 of the 23,165 new and relapse cohorts of 2018 were MDR/rifampicin resistant (RR).[2] Drug resistance surveillance data show that 2.5% among new pulmonary TB cases[3] and 27.6% of previously treated TB cases were estimated to have MDR/RR-TB in Cameroon.[4] The African continent accounts for over 80% of TB cases of the anti-TB drug resistance within the world,[5] but MDR-TB appears nearly absent from this continent, which, until recently, reported all-time low median levels of drug resistance TB. In Africa, about 2.7% of new and 14% of previously treated cases were diagnosed with drug resistance TB, respectively.[6]

In spite of so many researches on drug targets and drugs in TB, the disease remains to be a major cause of morbidity and mortality throughout the world.[7] Treatment of MDR-TB requires long-term therapy with a combination of multiple second-line drugs.[8] These drugs are associated with numerous adverse drug events (ADEs) that can also cause severe morbidity and mortality.[9] Although there are many drug targets reported in TB and many inhibitors proposed for those targets, more effective with less toxicity drug for TB are still being sorted.[7]

In Cameroon, virtually all TB cases are diagnosed and treated within a nationwide network of 256 TB diagnostic and treatment centers (DTCs) managed by the National TB Program (NTP). Rifampicin-sensitive cases are treated for 6 months with rifampicin-isoniazid-ethambutol-pyrazinamide,[10] whereas RR cases are treated for 9 months with rifampicin-isoniazid-ethambutol-pyrazinamide-kanamycin and ofloxacin,[11] which are less effective, more costly, and more toxic than first-line drugs.[8] The frequency, severity, and nature of these ADEs is a matter of concern.[12] Recently, new and repurposed drugs such as linezolid based have been shown to be effective in the treatment of MDR/RR-TB.[13] Although linezolid-based combination therapy is associated with improved culture conversion rate and rapid sterilization of Mycobacterium tuberculosis, it has substantial toxicity such as myelosuppression and peripheral neuropathy and may require the discontinuation of the drug during therapy.[13] An ADE is an injury resulting from medical intervention associated with a drug. This includes medication errors, adverse drug reactions, allergies, and overdoses. ADEs are one among the leading causes of morbidity and mortality within the health-care system.[14] Consequences of ADEs result in treatment disruption, treatment failure, and acquired resistance. All this adds up to the number of TB cases and more infrequently in the number of deaths.[12] Globally, studies have reported that the general prevalence of ADE-related hospitalization varies from 0.2% to 83.5%.[12],[14] Factors such as aging,[6] anemia,[15] MDR-TB medication,[16] overweight/obesity status,[6] and smoking history[15] are related to anti-TB adverse drug reactions. Major ADEs reported in several studies on second-line anti-TB drugs (SLDs) include drug induced, hepatitis, electrolyte disturbance, acute psychosis, acute kidney injury, peripheral neuropathy, and hypothyroidism.[6] Although these ADEs may be very frequent, they do not always result in temporary or permanent deferral of anti-TB treatment.[12] These findings suggest that ADEs could be better managed by supportive psychological and pharmacological therapy without disturbing the clinical effectiveness of anti-TB treatment,[12] unless the ADRs are fatal.

To the best of our knowledge, there is no study conducted on ADEs associated with SLDs for TB in Cameroon. Therefore, our study was aimed to assess the incidence and predictors of major ADE among patients on second-line anti-TB regimen treated under program conditions within the Littoral Region of Cameroon.


  Methods Top


A cross-sectional study was used to enroll 3302 participants from January 2016 to December 2017 from 39 DTCs distributed over the 24-health district within the Littoral Region of Cameroon.

Clinical parameters such as weight and height were obtained monthly to assess therapeutic success. Participants followed up within the intensive phase of treatment were carried out weekly by a clinical team for assessment of ADEs. Symptoms such as nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, and anorexia were monitored clinically to determine gastrointestinal disorders. Neurological symptoms within the extremities (feet and/or the hands) such as pains, burning, numbing, cold, or restless sensations tingling, problems with walking or tripping, and also the development of any sores or injuries to the feet were monitored.

Laboratory parameters at month (M) zero (M0) consisted of a line probe assay to exclude resistance to second-line drugs. Monthly smear microscopy and culture at M0, M3, M6, and M9 were carried out to monitory therapeutic success. Audiogram, creatinine, serum glutamic-oxaloacetate transaminase (SGOT), and serum glutamic-pyruvate transaminase (SGPT) were performed at M0, M3, M6, and M9 to determine audiometry, renal, and liver function disorders.

Blood (4–5 ml) was collected in EDTA tubes and plasma was obtained after centrifugation. HIV testing was done by transferring 0.5 ml of plasma to the absorbent pad of Determine HIV 1/2 test strip, and the appearance of bands on both the control and test well was considered positive. The appearance of a single band on the control well was considered negative and any single band on the test band was considered test invalid and the test procedure was repeated. Positive samples were confirmed on rapid SD BIOLINE HIV 1/2 3.0.

Creatinine and transaminase measurements were by the use of a spectrophotometer (Humalyzer 2000 Semi-Automated Analyzer).

Creatinine measurement was by Jaffe's method. Briefly, 0.2 ml of plasma was mixed with 3 ml of working reagent and its absorbance measured at 505 nm/green filter against standard and internal control (QC) tubes. The results were calculated by dividing the test absorbance with the standard absorbance and also the product multiplied by 6 mg/dl. The reference ranges for clinical interpretation of plasma creatinine was 0.7–1.4 mg/dl for male and 0.4–1.2 mg/dl for female.[17]

The two transaminases of diagnostic importance that were measured were the SGOT and SGPT. They were measured by colorimetric end-point method. The test procedure was similar for both SGOT and SGPT, where 0.1 ml of serum was mixed with 1.5 ml of working reagent and its absorbance measured at 510 nm/green filter against that of QC tubes. The results were recorded directly as absorbance, and the reference range of SGOT is <31 IU/L for females and <47 IU/l for males, whereas for SGPT, it is <32 IU/L for females and <41 IU/l for males.

An audiogram is a graph on which the audiometry results are plotted. It shows the lowest sound that an individual can hear at specific frequencies from the lowest to the highest. For audiometry measurements, the participants were asked to be comfortably seated in a standard silent room to avoid noise that might prevent the smooth measurement. The frequency sound measured in Hertz (Hz) was played by the audiometer (MADSEN Micromate 304, Otometrics, 2013, Denmark) with increasing loudness of 500, 1000, 2000, and 4000 Hz to determine at which intensity the patient was able to hear.

The average hearing impairment (AHL) attributed to ADEs were calculated by summing each ear frequency of 500, 1000, 2000, and 4000 Hz and dividing by 4. The values of the AHL were rounded up to the upper boundaries, and the grade for the ear with the highest value was considered. The degrees of AHL were rated according to the scale for adverse events by Piubello.[16]

The intensive phase of treatment (4 months) consisted of a seven-drug regimen including the second-line injectable kanamycin, moxifloxacin, isoniazid, clofazimine, ethionamide, and pyrazinamide. The continuation phase of treatment (5 months) includes moxifloxacin, clofazimine, ethionamide, and pyrazinamide. Treatment dose was adjusted for patient weight, in accordance with the national guide (10). ADEs were classified into four categories per their severity as follows (11): Grade 1 (mild): mild or transient discomfort without limitation of normal daily activities; no medical intervention or corrective treatment required. Grade 2 (moderate): mild-to-moderate limitation of normal daily activities; minimal medical intervention or corrective treatment required. Grade 3 (severe): marked limitation of normal daily activities; medical intervention and corrective treatment required; possible hospitalization. Grade 4 (life-threatening or permanent injury): extreme limitation of normal daily activities; medical intervention and corrective treatment required, in a hospital setting. ADEs were accessed by the help of some laboratory examinations and they were graded following the criteria in [Table 1].
Table 1: Laboratory examinations and the grading of adverse drug events

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Predictors such as demographics: sex and age; socioeconomic: marital status and monthly income (below and above 50.000 FCFA [approximately 100 USD]); clinical: fever, cough, weight loss, and night sweat; TB treatment history (yes or no), TB treatment category (new, relapse, failure, MDR-TB contact, and returning after lost to follow-up) and HIV status; and behavioral as cigarette smoking and alcohol consumption were measured, and multivariate analysis was used to determine their association with ADEs.

Data analysis was carried out using SPSS 17.0 (Statistical Package for the Social Sciences, Chicago, Illinois, USA). Univariate analysis was performed with Chi-square, and statistical significance was set at <0.05.

Authorizations for the study were obtained from the permanent secretary for the National TB Control Program and ethical clearance from the University of Douala Ethical Review Board.


  Results Top


A total of 3492 persons were enrolled during a cross-sectional study from 32 (82.1%) of the 39 CDTs in the Littoral Region of Cameroon. A total of 190 (5.6%) participants who had incomplete questionnaires were excluded. Among the 3302 who were tested, 1665 (50.4%) were positive for Mycobacterium tuberculosis, and out of which, 86 (5.2%) were resistant to rifampicin and thus eligible for second-line (MDR-TB) treatment. Among the 86, 10 (11.6%) refused to admit their status and eventually were not put on second-line treatment and 5 (5.8%) died before they could start their treatment. Overall, 71 (82.6%) of the 86 participants were assessed clinically at baseline. Six participants were excluded from the longitudinal analysis of ADEs due to high clinical values above the acceptable ranges (3 for auditory abnormalities, 2 for hepatotoxicity, and 1 for renal disorder). Finally, 65 participants were assessed for ADEs in this study.

The mean age of the study participants was 34.7 years (95% confidence interval = 32.2–37.2) and the mean creatinine, transaminases, and audiometry measurement increased significantly from initiation through the intensive phase of treatment and started dropping during the continuation phase of treatment, as illustrated on [Figure 1]
Figure 1: Changes in mean creatinine, serum glutamic-oxaloacetate transaminase, serum glutamic-pyruvate transaminase, and audiometry measurement over the course of treatment

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From the 65 patients, 72 ADEs were identified in 48 (73.8%) of them, and of which, 7 participants (14.6%) had at least one severe ADE (Grade 3). Participants experienced a median of 1.4 ADEs (interquartile range: 1–2) per patient. Gastrointestinal disorders were the most common (35 [46.6%]) of the 72 ADEs and were followed by auditory injuries (16 [22.2%]), hepatotoxicity (11 [15.3%]), neurological disorders (6 [8.3%]), and kidney disorders (4 [5.6%]) in this study.

The overall follow-up duration of this study was 11,250-person day (PDY). The incidence rate for ADEs was 4.3/1000 PDR. The incidence rate for gastrointestinal disorders, auditory injuries, hepatotoxicity, neurological disorders, and kidney disorders was 3.1, 1.4, 1.0, 0.5, and 0.2 (/1000PDY), respectively. The incidence of ADEs in the study population is illustrated in [Figure 2].
Figure 2: Incidence of adverse drug per 1000-person day in the study area

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Three drugs were incriminated with 72 ADEs (kanamycin [65 (90.3%)], isoniazid [4 (5.6%)], and ethambutol [3 (4.2%)]) and drug dosages were reduced in 18 (27.7%) and replaced completely in 2 (3.1%) of the 48 participants who experience ADE. The majority 18 (90%) of the 20 requiring dosage modification or drug replacement occurred during intensive phase of treatment. Most (29 [60.4%]) of those who developed ADEs did so during the first 2 months of drug initiation.

Those older than 30 years were more likely to develop ADEs than those younger. ADEs were observed in 52 (80%) and 50 (76.9%) of all those who were previous cigarette smokers and had TB treatment exposure, respectively. Earning 100 USD per month was significantly associated with ADEs, as illustrated in [Table 2].
Table 2: Predictors of developing adverse drug events during second-line antituberculosis treatment

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  Discussion Top


This study reveals that 74% of our study participants experienced at least one ADEs during the therapeutic period of 9 months. This was higher than the 35.3% reported by Schnippel et al.[18] in 2016, and 57.3% reported by Wu et al.[19] in two studies carried out in South Africa and the 52% reported by Hoa[20] in Vietnam. This was, however, lower than the 99% reported by Schnippel et al.[21] in 2015. Our study reported lower rates of ADEs than that of Schnippel et al.[21] probably because after the intensive phase, our participants were followed up in ambulatory and also because during the monthly visits to the outpatient MDR-TB treatment unit, participants were prompted to self-report ADEs. This may have resulted in an underreporting of ADEs, particularly those that were mild to moderate. Although the most common ADE reported in our study was gastrointestinal disorders (bleeding, gastritis, or nausea) (52.1%), similar to that reported in the Latvian study,[22] where the most commonly reported ADEs were nausea (58%), vomiting (39%), and abdominal pain (24%), this was not the case with other studies as the most observed ADE varies across different studies. In the Vietnam[20] study, the most encountered ADE was arthralgia or joint pain (36%), followed by gastrointestinal disturbance (14%) as the most common ADEs. Another study in Turkey[23] reported that the most frequently ADE was ototoxicity (42%) followed by psychiatric disorders (21%). In this study, ADEs were associated with poor treatment outcomes. Given the variation in the reporting of ADEs to second-line anti-TB drugs (SLDs) by different studies, it is imperative that the staff within the NTP be trained to rapidly recognize and manage common adverse events associated with the use of SLDs, especially as some ADEs such as nausea and vomiting may appear mild to moderate but can have an impact on both adherence and effectiveness of treatment resulting in lower probability of treatment success and consequently higher risk of acquired drug resistance.

The majority of ADEs were recorded during the intensive phase (first 4–6 months) of treatment, and kanamycin was the most incriminated drug and was associated with 90.3% of those who developed ADEs. In this study, the risk of experiencing ADEs in participants with TB/HIV comorbidity was higher than that of participants without the comorbidity. This result was similar to studies carried out in Peru,[24] Ethiopia,[6] and South Africa,[25] which showed that patients with any type of comorbid conditions were at increased risks for developing ADEs. This could be due to the fact that the pill burden and drug–drug interactions put patients at increased risk for developing different adverse drug reactions and patients with additional medical condition might have compromised immunity and poor tolerance to drugs.[26]

Those older than 30 years were three times more likely to develop ADEs than those younger. Studies have shown that aging is a factor that reduces muscle mass and water content with a relatively increase in the proportion of total body fat. These changes influence the volume of distribution of many drugs which can, in turn, increase the risk of developing ADEs if doses are not adjusted.[27] Some lipophilic drugs generally have a larger volume of distribution with prolonged elimination half-life in older patients compared with younger patients.[28] Conversely, for hydrophilic drugs, the volume of distribution is reduced; this may also result in toxicity if drug doses are not adjusted, particularly if there is concomitant renal impairment which may impede drug excretion.[28] In this study, ADEs were observed in 73.7% and 86.5% of all those who were coinfected with TB/HIV and those who consumed alcohol, respectively, and placed on second-line treatment.


  Conclusions Top


The incidence of ADEs was high in the study, and most of it occurred during the intensive phase of treatment. Kanamycin was associated with almost all the ADEs. We recommend that it is imperative to train the clinical staff and all patients on SLDs to rapidly identify and report the mildest symptoms of ADE because this could have an impact on both adherence and treatment effectiveness; that.

Acknowledgments

We give special thanks to staffs at the MDR-TB treatment center in Dibamba for their cooperation and support.

Ethics approval and consent to participate

Consent of participants was sort at the MDR-TB treatment center where they were counseled and educated on the length and toxicities of SLDs for TB, and for participants younger than 21 years, consent was obtained from parent/legal representative. Ethical clearance was obtained from the Institutional Ethics Committee for Research on Humans of the University of Douala with ref N: 1257 IEC-Udo/02/2016/T

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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