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  RESEARCH Open Access Occurrence and clinical management of moderate-to-severe adverse events duringdrug-resistant tuberculosis treatment: aretrospective cohort study Evans L Sagwa 1,2* , Aukje K Mantel-Teeuwisse 2 and Nunurai C Ruswa 3 Abstract Objectives:  To determine the incidence of symptomatic moderate-to-severe adverse events during treatment of drug-resistant tuberculosis, and to compare their risk and outcomes by patients ’  human immunodeficiency virus(HIV) co-infection status. Methods:  We conducted a retrospective cohort analysis of patients treated for drug-resistant tuberculosis betweenJanuary 2008 and February 2010. Routinely, clinicians monitored and managed patients ’  response to treatment untilits completion. Any symptomatic adverse event observed by the clinician or reported by the patient was recordedin the standard patient treatment booklet of the National Tuberculosis and Leprosy Programme. There were 18symptomatic adverse events routinely monitored. Depending on the nature of the medical intervention needed,each was graded as mild, moderate or severe. Data were extracted from the patient treatment booklet using astructured form, then descriptive, bivariate and Cox proportional hazard analysis performed, stratified by patients ’ HIV infection status. Statistical associations were done at the 5% level of significance and reported with 95%confidence intervals. Results:  Fifty seven (57) patients with drug-resistant tuberculosis were identified, 31 (53%) of whom were HIV co-infected. The cumulative incidence of moderate-to-severe adverse events was 46 events in 100 patients. HIV co-infected patients experienced more moderate-to-severe adverse events compared with the HIV uninfectedpatients (median 3 versus 1 events,  p  = 0.01). They had a four-fold increase in the cumulative hazard of moderate-to-severe adverse events compared with the HIV uninfected patients (HR = 4.0, 95% CI 1.5  –  10.5). Moderate-to-severe adverse events were the main determinant of a clinician ’ s decision to reduce the dose or to stop thesuspected offending medicine (RR = 3.8, 95% 1.2-11.8). Conclusions:  Moderate-to-severe adverse events are common during drug-resistant tuberculosis therapy. They aremore likely to occur and to persist in HIV co-infected patients than in HIV uninfected patients. Clinicians shouldemploy various strategies for preventing drug-induced patient discomfort and harm, such as reducing the dose orstopping the suspected offending medicine. Managers of tuberculosis control programmes should strengthenpharmacovigilance systems. We recommend a more powered study for conclusive risk-factor analysis. Keywords:  Medication safety, Second-line anti-tuberculosis drugs, Pharmacovigilance, Adverse effects, TB/HIV co-infection, Namibia * Correspondence: esagwa@gmail.com 1 School of Public Health, University of the Western Cape, Cape Town, SouthAfrica 2 Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University,Utrecht, the NetherlandsFull list of author information is available at the end of the article © 2014 Sagwa et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the srcinal work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article,unless otherwise stated. Sagwa  et al. Journal of Pharmaceutical Policy and Practice  2014,  7 :14http://www.joppp.org/content/7/1/14  Introduction The burden of tuberculosis (TB) disease in Namibiaremains high, with a case notification rate of 545 casesper 100,000 population in 2012 [1]. The prevalence of drug-resistant tuberculosis (DR-TB) in the country, esti-mated at 20.1 cases per 100,000 TB patients, combinedwith the high human immunodeficiency virus (HIV) co-infection rate of about 50%, is a major public healthconcern for the National Tuberculosis and Leprosy Programme (NTLP) [1].Both DR-TB and HIV infections need to be treated,otherwise, the patient may not survive for too long [2,3]. The adverse effects of second-line anti-tuberculosis andantiretroviral medicines pose a unique challenge in thecombined treatment of the two infections [2,3]. Moderate- to-severe adverse events can cause patients ’  intolerance tosecond-line anti-tuberculosis medicines and antiretroviralmedicines, possibly compromising DR-TB and HIV treat-ment outcomes. Such intolerance may require the clin-ician treating the patient to make specific medicine dosageadjustments, regimen changes or stop the treatment [4,5]. Similarly, treatment of HIV with highly active antiretro- viral therapy (HAART) is associated with various adverseeffects, some of which may overlap with those of second-line anti-tuberculosis medicines [2,3,6]. This paper is the third and last of a series of papers[7,8] that we have published based on a dataset on the occurrence of adverse events during treatment of DR-TBin Namibia, each paper addressing a different aspect of the adverse events epidemiology. The first paper de-scribed the burden of adverse events during treatment of DR-TB, [7] while the second paper compared, by HIV co-infection status, the risks and the risk-factors for thecommonly observed adverse events [8]. Apart from ourresearch highlighted above, there is limited scientific lit-erature on the incidence, clinical management and theoutcomes of moderate-to-severe adverse events amongpatients on DR-TB therapy in Namibia.In this paper, we describe the cumulative incidence andthe actions taken by clinicians to manage the moderate-to-severe adverse events occurring during DR-TB treat-ment. Secondly, we compare the risk and outcomes of these moderate-to-severe adverse events, by patients ’  HIV co-infection status. Methods Study design This was a retrospective observational cohort study of consecutive patients treated for DR-TB between January 2008 and February 2010 at the Kondja DR-TB treatmentward in the Walvis Bay District of Namibia. All theDR-TB patients treated at this facility during the specifiedperiod were included in the study. Setting The study was conducted at the Kondja DR-TB treat-ment ward, which is a 25-bed district hospital DR-TBtreatment facility serving the entire Erongo region of Namibia. The Erongo region had the second largestnumber of patients on DR-TB treatment in Namibia atthe time of the study. In this ward, patients with micro-biologically confirmed DR-TB infection were placed onsecond-line intensive phase treatment that included par-enteral amikacin, kanamycin or capreomycin for a mini-mum of four months, until two sputum smears and twosuccessive cultures turned negative [7,9]. Clinicians de- signed individualized regimens and calculated daily doses of each medicine based on patients ’  body weight,in accordance with the national TB treatment guidelinespublished in 2006 [9]. The HIV co-infected patients were,additionally, treated with HAART regimens that com-prised of lamivudine in combination with either zidovu-dine (AZT) or stavudine (d4T) and efavirenz (EFV) ornevirapine (NVP) [9].The susceptibility of   M. tuberculosis  to anti-TB medicineswas tested by the Namibia Institute of Pathology using theliquid culture MGIT 960 system (BACTEC ™  MGIT ™  960Mycobacteria Culture System, Becton Dickinson, New Jersey, USA) on all  M. tuberculosis  confirmed cultures, forsusceptibility to isoniazid, rifampicin, streptomycin andethambutol. All isolates of   M. tuberculosis  found to be re-sistant to rifampicin or isoniazid were sent to the NationalHealth Laboratory Service in South Africa for testing of resistance to kanamycin, capreomycin, amikacin, cipro-floxacin, levofloxacin and ethionamide.Routinely, during DR-TB treatment, patients were closely monitored and supervised by the clinician until com-pletion of treatment. Any clinician-observed or patient-reported symptomatic adverse events were recorded in thestandard patient treatment booklet designed by the NTLP.At the time of the study, the DR-TB patient treatmentbooklet listed 18 symptomatic adverse events that wereroutinely monitored during treatment: abdominal pain,constipation, hearing loss (decreased hearing), depression,diarrhoea, dizziness, fatigue, fever, headache, joint pain,nausea, neuropathy, psychosis, rash, tinnitus, tremors, vision changes and vomiting [9]. According to the DR-TBpatient treatment booklet (Additional file 1), the severity of an adverse event could be classified into three grades.Grade 1 were the mild adverse events, requiring nomedical intervention; Grade 2 were the moderate ad- verse events, requiring palliative [or adjunctive] inter- vention; while Grade 3 were the severe adverse events,requiring a change in treatment or its discontinuation[9]. Each observed adverse event was graded by theattending clinician as mild, moderate or severe as ex-plained above and was managed according to the sever-ity grading. Sagwa  et al. Journal of Pharmaceutical Policy and Practice  2014,  7 :14 Page 2 of 8http://www.joppp.org/content/7/1/14  Ethical considerations Ethical approval of the study protocol was obtained fromthe research unit of the Ministry of Health and SocialServices of Namibia (MoHSS)  –  Ref 17/3/3/AP and theHigher Degrees Committee of the University of theWestern Cape, South Africa, both of which are institu-tional review boards. Data collection The lead researcher (corresponding author) collecteddata from patients ’  DR-TB treatment booklet using astructured form. No personal identifiers were recorded,to maintain the anonymity and the confidentiality of thepatients. The primary study outcome was the occurrenceof any adverse event during DR-TB treatment. The sec-ondary outcome was the occurrence of moderate-to-severe adverse events. Further, detailed characterizationof each moderate-to-severe adverse event was con-ducted, which included: its description, time-to-onset,severity grading, duration, actions taken to manage theadverse event, and the outcome of the adverse event. Definition of terms In this study, DR-TB included both poly- and multidrugresistant forms of   M. tuberculosis . Poly drug-resistance wasdefined as the resistance of   M. tuberculosis  to either isonia-zid or rifampicin and other first-line anti-tuberculosismedicines, while multidrug resistance was the resistanceto at least both isoniazid and rifampicin [9]. Data analysis We limited our statistical analyses to descriptive andunivariate analysis, due to the small sample of DR-TBpatients that was realized. We couldn ’ t perform multi- variable analyses because of the few degrees of freedomof the small sample. We therefore calculated absoluteand relative frequency counts, measures of central ten-dency (mean and median) and measures of dispersionincluding range, interquartile range and standard devi-ation. We applied two-tailed Student ’ s T-tests to com-pare group differences in age and weight after testing fornormality. For non-normally distributed variables suchas the number of adverse events observed, comparisonswere made by the non-parametric Mann – Whitney/Wilcoxon two sample test. We compared proportionsand categorical variables using the Chi-square or Fisherexact test respectively, depending on whether or not theexpected value for a cell in the cross-tabulation wasgreater than five.Associations between exposure and outcome variableswere assessed using 2×2 contingency tables, with furtherstratification by HIV infection status. In addition, Kaplan-Meier and Cox proportional hazard analysis were per-formed to generate hazard ratios. All the analyses weredone in Epi Info 3.4.3. (November 2007, Centers for Dis-ease Control and Prevention, Atlanta, USA) and reportedas point estimates, 95% confidence intervals (95% CI) and  p -values. However, the Kaplan-Meier plot was drawn usingthe Statistical Package for the Social Sciences (SPSS®) forWindows, version 12.0.1 (IBM Corporation, New York,USA). A  p -value of less than 0.05 was considered to bestatistically significant. Lastly, we used Microsoft Excel®(Microsoft office 2010, Microsoft Corporation, Redmond,Washington State, USA) to draw charts and tables. Results The proportion of DR-TB patients who experienced any adverse event was 51/57 (89%). Of these 51 patients, 26(51%) experienced at least one moderate-to-severe ad- verse event. A medical intervention was made to managethe adverse event in 29 (57%) of the patients. Thesemedical interventions included reducing the medicinedose or stopping the suspected offending medicine in 15patients (29%), using other adjunctive medicines to treatthe adverse event(s) in 14 patients (27%), or completely changing the DR-TB treatment regimen in 9 patients(18%). There were 20/51 (39%) patients who experiencedpersistent adverse events that lasted for three months ormore, while 15/51 (29%) patients were yet to recover fromtheir adverse events by the study end date (Figure 1).The distribution of the patients ’  demographic and clin-ical characteristics was generally similar between the 26DR-TB patients who experienced at least one moderate-to-severe adverse event compared to the 25 who experi-enced at least one mild adverse event (Table 1). However,the HIV co-infection rate was notably higher among thepatients who experienced at least one moderate-to-severeadverse event, compared with those who experienced only mild adverse events (69.2% versus 40%,  p =0.04).Overall, the DR-TB patients co-infected with HIV ex-perienced more moderate-to-severe adverse events com-pared with the HIV uninfected patients, with a medianof 3 adverse events versus 1 adverse event respectively (  p =0.01), as depicted in Table 2. Eighteen of the 26 DR-TBpatients who experienced at least one moderate-to-severeadverse event (69%), were HIVco-infected (Figure 2).The cumulative incidence of moderate-to-severe ad- verse events in the entire cohort was 26 events out of 57patients (46 events in 100 patients). By comparison, thecumulative incidence of moderate-to-severe adverseevents amongst the HIV co-infected patients was 18events out of 28 patients (64 events in 100 patients) whileit was 8 events out of 23 patients (35 events in 100 pa-tients) amongst the HIV uninfected patients, (  p =0.04).In a time-to-event analysis using a Kaplan Meier curveand Cox proportional hazards analysis, the DR-TB pa-tients who were co-infected with HIV had a four-foldcumulative hazard of experiencing moderate-to-severe Sagwa  et al. Journal of Pharmaceutical Policy and Practice  2014,  7 :14 Page 3 of 8http://www.joppp.org/content/7/1/14  adverse events compared with the HIV uninfected pa-tients (HR =4.0, 95% CI 1.5  –  10.5,  p = 0.006), Figure 3.In terms of medicines exposure, the DR-TB patients inour cohort were treated with individualized regimens,based on the susceptibility of the  M. tuberculosis  to spe-cific second-line anti-TB medicines. In total, the patientswere treated with 15 different second-line anti-TB medi-cines, while the HIV infected patients were additionally treated with HAART regimens, which consisted of lami- vudine in combination with either zidovudine (AZT) orstavudine (d4T) and efavirenz (EFV) or nevirapine (NVP).None of the second-line anti-TB or antiretroviral medi-cines was statistically significantly associated with the oc-currence of moderate-to-severe adverse events (Table 3).However, amikacin, ciprofloxacin and ethambutol tendedto have a much higher risk when compared with the othersecond-line anti-TB medicines.We further explored the association between the oc-currence of moderate-to-severe adverse events, the spe-cific medical interventions made to manage them andtheir specific outcomes. From a univariate analysis onthe entire cohort, we found that moderate-to-severe ad- verse events determined whether the clinician chose toreduce the dose or to stop a specific DR-TB medicine,the risk ratio (RR) for the association being 3.8 (95% CI1.2-11.8,  p =0.01). Upon stratification to assess for con-founding or effect modification by HIV infection status,the association remained similar between HIV infectedand HIV uninfected patients (RR =4.2 and RR =4.1 re-spectively) (Table 4).There were HIV stratum-specific differences in theconnection between occurrence of moderate-to-severeadverse events and those that lasted for three or moremonths. The risk ratios were RR =3.6 (95% CI 1.03-12.5,  p = 0.009) for the HIV infected sub-group versus RR=1.9(95% CI 0.5-7.2,  p =0.33) for the HIV uninfected one,demonstrating effect modification by HIV infection status(Table 4).On the contrary, the occurrence of moderate-to-severeadverse events was not a determinant of the clinician ’ s All patients treated for DR-TB (N=57)HIV infected (n=31)HIV uninfected (n=26)Any adverse event (n=51)No adverse event (n=6)Moderate/ severe adverse events (n=26)Mild adverse events (n=25)Medical intervention made to manage AE (n=29)(i) Dose reduced/medicinestopped (n=15)(ii) Adjunctive therapy (n=14)(iii) Regimen changed (n=9)Adverse events lasting 3 months (n=20)Adverse events not yet resolved(n=15) Figure 1  Flow diagram of DR-TB treatment, occurrence and outcomes of adverse events.  Legend for Figure 1: DR-TB=drug resistant tuberculosis;HIV=Human immunodeficiency virus; AE=adverse event. Table 1 Demographic and clinical characteristics of the patients, by adverse event severity grading Adverse events by severity grading (N=51)Moderate-to-severe events (n=26) Mild events (n=25)  P  -value Gender: Male, n (%) 16 (61.5%) 15 (60.0%) 0.91Age: mean ± SD, yrs 34.1 ± 8.3 35.0± 10.2 0.71Weight: mean± SD, kg 51.4± 10.3 53.9± 12.3 0.45HIV co- infection, n (%) 18 (69.2%) 10 (40%) 0.04HAART, n (%) 5 (19.2%) 7 (28%) 0.46Duration (days) of therapy; median (IQR) 183.5 (173 – 243) 185 (175.5-212) 0.81Number of drugs in intensive phase regimen; median (IQR) 5 (5 – 6) 5 (5 – 6) 0.61 SD=standard deviation; yrs =years; kg=kilogrammes; HIV=human immunodeficiency virus; HAART=highly active antiretroviral therapy; TB=tuberculosis;IQR =interquartile range. Sagwa  et al. Journal of Pharmaceutical Policy and Practice  2014,  7 :14 Page 4 of 8http://www.joppp.org/content/7/1/14
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