Tuberculosis Research and Treatment

Tuberculosis Research and Treatment / 2014 / Article

Research Article | Open Access

Volume 2014 |Article ID 626797 | https://doi.org/10.1155/2014/626797

Driss Soussi Tanani, Amina Tebaa, Raja Benkirane, Kenza Bennani, Ghali Iraqi, Abdelmajid Soulaymani, Rachida Soulaymani Bencheikh, "Pharmacovigilance and Moroccan Tuberculosis Public Program: Current Situation", Tuberculosis Research and Treatment, vol. 2014, Article ID 626797, 6 pages, 2014. https://doi.org/10.1155/2014/626797

Pharmacovigilance and Moroccan Tuberculosis Public Program: Current Situation

Academic Editor: Jacques Grosset
Received26 Feb 2014
Accepted25 May 2014
Published12 Jun 2014

Abstract

The objective of this work is to demonstrate the interest of integration of pharmacovigilance in Moroccan Tuberculosis Control Program (MTCP). Design and Data Collection. The integration of pharmacovigilance in MTCP was conducted in October 2012 with the Global Fund support. We compared the reports notified before and after this integration (period 1: January 2010–October 2012; period 2: October 2012–December 2013). The detection of signals was based on the Information Component available in VigiMine. We used the SPSS version 10.0 and MedCalc version 7.3 for data analysis. Results. The average number of spontaneous reports increased from 3.6 to 37.4 cases/month (). The average age was years; the sex ratio was 0.8. Hepatic reactions (32.7%) predominated during the first period, while skin reactions (24.1%) were in the second period (), and 40.9% of cases in the first period were serious against 15.8% in second period (). Nine signals were generated (hepatic enzyme increase, cholestasis, jaundice, arthralgia, acne, lower limb edema, pruritus, skin rashes, and vomiting). Conclusion. The integration of pharmacovigilance in Moroccan Tuberculosis Control Program improved the management of ADRs and detected new signals of antituberculosis drugs.

1. Introduction

Tuberculosis (TB) remains a major public health problem globally. Clinicians treating TB patients around the world know these medicines well and are usually well aware of their associated adverse drug reactions (ADRs) [1]. The occurrence of these reactions is known to be frequent. The TB patient on treatment is taking more than one anti-TB medicine simultaneously and regimens last from many months to 2 years or more. This increases the likelihood of ADRs, some of which are severe. A recent study has shown that two-thirds of such patients have had at least one medicine stopped temporarily or permanently as a result of ADRs [2]. These events may damage public confidence in any national treatment program and affect patient adherence [3, 4]. Patients who stop taking anti-TB medicines pose a risk to themselves and to others. The generation of drug resistance is a very real risk.

Tuberculosis in Morocco remains also a public health problem with an average incidence of 83.5 cases per 105 inhabitants in 2011. Resistant TB form represents 1.3% of the whole cases [5]. As public health programmes (PHPs) are extended to the more vulnerable populations such as the young, the elderly, pregnant women, and people with malnutrition, the chances of developing ADRs and interactions will increase. In addition, health practitioners and the public need more information about the potential benefit, rationality of use, and risk of the medicines given.

Recently there have been some initiatives within countries or under the leadership of WHO, to create and develop subsystems for pharmacovigilance (PV) to monitor the specific products used in their PHPs. Morocco is among the first countries which received grants from the Global Fund to strengthen pharmacovigilance in AIDS and TB [6].

The global objective of this work is to demonstrate the interest of integration of PV in Moroccan Tuberculosis Control Program (PV-MTCP). The specific objectives are as follows:(i)to promote ADRs spontaneous reporting;(ii)to analyze and evaluate ADRs;(iii)to recommend regulatory action for minimization of the risks;(iv)to initiate studies to investigate significantly suspect reactions;(v)to alert TB health practitioners, manufacturers, and the public to new signals of ADRs.

2. Methods

2.1. Study Design and Setting

It was a retrospective study (January 1, 2010–October 11, 2012) with a passive PV and without Global Fund support, compared with a prospective study (October 11, 2012–December 2013), conducted in all Moroccan TB diagnosis centers (MTDC) which are in charge of treating TB patients, after integrating PV-MTCP. These MTDC exist in all cities and receive about 27000 TB patients per year. The comparison between the 2 periods concerned the number of reports, methods used for collecting ADRs (spontaneous reporting in period 1 versus intensive pharmacovigilance reporting in period 2), nature, and seriousness of ADRs.

2.2. Study Population

Patients treated for TB and only who reported one or more ADRs were included in this study. TB patients who did not present ADRs were excluded from this study.

2.3. Data Collection

We conducted several sessions of intensive PV to report anti-TB induced ADRs for all Moroccan TB health practitioners and we validated a system of spontaneous reporting of ADRs between the MTDC and the Moroccan Pharmacovigilance Center (MPVC). Each notified case is handled by the OMS accountability method [7] that determines the relationship of cause to effect; then all cases are sent to the international database (Vigiflow) [8]. We established an electronic registry of ADRs reporting which one serves as a tool to provide answers to the different notifiers and change the information between the MPVC and them.

2.4. Analysis

The data were collected using Microsoft Excel software (version 5.1), and variables were described as percentage or mean (±SD). Qualitative data were compared using Chi-2 test or Fisher exact test. Quantitative data were compared using Student’s -test. The statistical significance level was set at . Analysis was performed using SPSS (version 10.0) and MedCalc (version 7.3) Software.

The detection of signals was based on the Information Component (IC) available in Uppsala Monitoring Center (UMC) software VigiMine [9], method of Bayesian Confidence Propagation Neural Network used by UMC for automatic generation of signals: Adverse drug reaction is considered a signal if the IC025 > 0: the probability of observed ADRs is greater than the probability of expected ADRs (IC025: Information Component within a range of 95% confidence).

3. Results

The international database VigiSearch [9] during the global period of study (January 2010–December 2013) showed that Morocco with an average TB incidence (50–100 cases/105 inhabitants) has recorded 927 ADRs (Table 1).


Country Number of reportsTB incidence (/105)

Republic of Korea 4650100–300
India 2960100–300
USA 1076<24
Morocco 92750–100
France 302<24
South Africa 191>300
Russian Federation 70100–300
Tunisia 85<24

3.1. Descriptive Study: General Information

608 cases were reported (927 ADRs) during the study (January 2010–December 2013). The average age of patients was years with a sex ratio of 0.8. The most prescribed anti-TB drug was ERIP-K4 (83.7%) since it contains 4 combined anti-TB drugs (Ethambutol, Rifampicin, Isoniazid, and Pyrazinamide) followed by Riniazide 10.1% (Rifampicin, Isoniazid) as maintenance treatment. Accountability of cases according to the WHO method showed that 5% had a certain relationship of cause to effect, 15% had a probable relationship, and 80% had a possible relationship. 140 of the cases were serious (23%) with 8 deaths (1.3%), 21 cases had a commitment prognosis (3.4%), 4 cases developed sequelae (0.6%), and 107 cases required hospitalization or prolongation of hospitalization (17.5%). The outcome was favorable in 47.2% of cases, 16.2% were healing, 35.2 were unknown, and 1.3% died.

For fatal cases, there were 3 women aged between 20 and 29 years: TB MDR with lower limb edema, lymph node TB in a pregnant woman with fulminant hepatitis, and pulmonary TB with toxic epidermal necrolysis; there were 5 men aged between 28 and 70 years: TB MDR with lower limb edema, pulmonary TB with hepatic encephalopathy, multifocal TB with cytolytic hepatitis, pulmonary TB with cholestatic hepatitis, and TB + heart failure with fulminant hepatitis (Table 2).


Age (year) SexIndication ADR Accountability

20FMultiresistant TB Lower limb edema Possible
30MMultiresistant TB Lower limb edema Possible
28MPulmonary TB Hepatic encephalopathy Probable
70MMultifocal TB Cytolytic hepatitis Possible
44MPulmonary TB Cholestatic hepatitis Possible
MTB + heart failure Hepatitis Possible
29FLymph node TB + pregnancyFulminant hepatitisProbable
27FPulmonary TBLyell syndrome Possible

3.2. Descriptive Study: Nature of ADRs (Table 3)

System Organ Class (disorders) Period 1
(%)
Period 2
(%)

Skin and appendages disorders86 (26.3)145 (24.2)NS
Gastrointestinal system disorders29 (8.9)126 (21)0,007
Liver and biliary system disorders107 (32.8)87 (14.5)NS
General disorders12 (3.7)86 (14.4)0,0007
Central and peripheral nervous system 42 (12.9)46 (7.7)NS
Musculoskeletal system disorders8 (2.4)36 (6)0,03
Psychiatric disorders 6 (1.8)20 (3.4)0,04
Hearing and vestibular disorders010 (1.7)
Respiratory system disorders010 (1.7)
Metabolic disorders 21 (6.4)9 (1.5)0,02
Platelet, bleeding, and clotting disorders 5 (1.5)6 (1)NS
Endocrine disorders06 (1)
Vision disorders05 (0.8)
Heart rate and rhythm disorders 2 (0.6)3 (0.5)NS
White cell disorders 2 (0.6)2 (0.3)NS
Red blood cell disorders 2 (0.6)1 (0.1)NS
Urinary system disorders 5 (1.5)1 (0.1)NS
Reproductive disorders01 (0.1)

Total327 (100)600 (100)

NS: not significant.

The majority of ADRs occurred during the first month after starting treatment with a difference depending on the nature of the ADRs (Figure 1). ADRs of liver and biliary system disorders (32.8%) predominated in period 1 with cytolytic hepatitis as the most predominant symptom followed by skin and appendages disorders (26.3%) with pruritus as the most predominant symptom, while ADRs of skin and appendages’ disorders predominated in period 2 (24.2%) followed by ADRs gastrointestinal system disorders (21%) with epigastric pain and vomiting as the most predominant symptom (Table 3).

3.3. Analytic Study

We compared the notification before and after PV-MTCP. The average number of reports increased from 3.6 to 37.4 cases/month (). The System Organ Class of ADRs reported during the first period concerned mainly liver and biliary system disorders (32.8%) because prescribers were reporting mainly serious ADRs, while skin and appendage system disorders (24.2%) of ADRs were predominantly reported in the second period.

New ADRs occurred in period 2 as ADRs of hearing and vestibular system disorders, respiratory system disorders, endocrine system disorders, visual system disorders, and reproductive system disorders (Table 3).

The comparison of seriousness cases before and after integration of PV-MTCP showed that in period 1 there were more hospitalization (28.9%) and development life-threatening (9.6%) (Table 4). The comparison of ADRs outcome before and after integration of PV-MTCP showed that in period 2 the outcome of ADRs was more favorable with less unknown cases but without significant difference (Table 5).


SeriousnessPeriod 1
(%)
Period 2
(%)

Hospitalization/prolonged51 (28.9)56 (13)<0,001
Life-threatening17 (9.6)4 (1)<0,001
Sequelae2 (1.2)2 (0.4)NS
Death2 (1.2)6 (1.4)NS

Total72 (40.9)68 (15.8)<0,001

NS: not significant.

EvolutionPeriod 1 (%)Period 2 (%)

Favorable41.852.7NS
Ongoing15.616.9NS
Unknown41.429NS
Lethality1.21.4NS

Total100100

NS: not significant.
3.4. Signals Detection

The signal detection was focused on the cases related to combined anti-TB form (ERIP-K4) recorded in VigiMine. We found 875 ADRs related to this combination; 268 of them were issued from Morocco (30.6%). 18 international signals have been generated; 11 of them were from Morocco (Table 6).


Nature of Signal International IC025Moroccan IC025

Hepatitis*3.690.12
Increase hepatic enzymes2.852.79
Jaundice2.681.25
Cholestatic hepatitis*2.161
Acne1.540.67
Arthralgia1.542.54
Vomiting1.330.76
Pruritus 1.141.78
Abdominal pain0.600.33
Periperal neuropathy*0.410.18
Peripheral edema0.141.98

Critical ADRs signal.

4. Discussion

The international database (Vigiflow) during the period of study (January 2010–December 2013) showed that Morocco with an average TB incidence (50–100 cases/105 inhabitants) has recorded 608 cases (927 ADRs). 176 cases were reported (327 ADRs) before PV-MTCP (January 2010–October 2012) and 432 cases were reported (600 ADRs) after PV-MTCP (October 2012–December 2013). USA is the best notifier country (1076 ADRs) with a low incidence (<24/105 inhabitants) and South Africa is the worst notifier country (191 ADRs) with the high incidence (>300/105 inhabitants). However, Republic of Korea and India have the highest rate of notifications (4650 and 2960 ADRs, resp.) due to their high incidence (100–300 cases/105 inhabitants), Table 1.

This increase of ADRs in period 2 was due to the effective integration of PV in the MTCP with awareness of the majority of anti-TB prescribers and involvement for spontaneous reporting of TB ADRs and feedback with practical procedures of ADRs management are regularly sent to anti-TB prescribers to motivate them to reporting ADRs.

In our study, females had a higher incidence of ADRs. In general, females are at a higher risk of developing ADRs [10]. It might be because they pass through life stages like pregnancy, menarche, and so forth, which modify the drug response [11]. Studies from UK and Canada also reported females to have a significantly higher incidence of ADRs due to anti-TB drugs [12, 13]. This suggests the need for special precautions while prescribing anti-TB drugs to females.

We compared the average time of onset of cutaneous, hepatic, and neurological ADRs. Cutaneous ADRs appeared first with an average time of days. Hepatic and neurological ADRs are with almost identical average time ( and days) but with a wide standard deviation for neurological ADRs (Figure 1). Cutaneous ADRs appeared first because their mechanism is often immunoallergic against hepatic ADRs and neurological ADRs take more time to appear. The majority of ADRs occurred during the first month after starting treatment requiring more vigilance during this period regardless of the nature of ADRs.

Onset of the ADRs is an important factor helpful in early detection of the ADRs. Also in studies from India [14] and from Nepal [15] more than half of ADRs occurred within the first 30 days after starting TB treatment. It is essential for the healthcare professionals to counsel the patients regarding the early identification of ADRs in the first few weeks. Regular monitoring of the patients during these initial weeks might be essential for early detection of ADRs.

On the severity of ADRs, cases of period 2 were significantly less severe than period 1 (15.8% versus 40.9%, ) with less hospitalization (13% versus 28.9%, ) and less development life-threatening (1% versus 9.6%, ). Eight patients died (1.3%) with an average age of years and a male sex ratio = 1.6, among which 5 died by hepatic complications, 2 had a multiresistant TB, and one died by Lyell syndrome (Table 2). Twenty-one cases (3.4%) had ADRs development life-threatening, and 4 cases developed sequelae 0.6% (2 left deafness, 2 ataxo-spasmodic diseases), Table 4.

In Morocco, the average of TB incidence has stagnated during recent years, about 81 cases per 100000 inhabitants [16]; then the increase of ADRs during period 2 is mainly due to the integration PV-MTCP. The reporters during the first period were in the majority from university and provincial hospitals, but in the second period they were mainly from MTDC. Among the 16 regions of Morocco, 7 were involved in the reporting of ADRs in the first period, whereas 14 regions were engaged in the second period. The System Organ Class of ADRs reported during the first period concerned mainly liver and biliary system disorders because the physicians reported mainly serious ADRs as hepatitis, while skin and appendage system disorders of ADRs were predominantly reported in the second period. This second period is quite rich in ADRs because it has been active pharmacovigilance which forced prescribers to notify all ADRs. There was a significant increase of reports in gastrointestinal, general, musculoskeletal, and psychiatric system disorders between 2 periods but a significant decrease of reports in metabolic system disorders because the notifications during the first period emanated mainly from university hospitals (Table 3).

There were new ADRs of reproductive, vision, respiratory, hearing, and vestibular and endocrine disordersnotified in the second periodafter PV-MTCP reflecting the interest of active pharmacovigilance.

The comparison of ADRs evolution before and after integration of PV-MTCP showed that in period 2 the outcome of ADRs was more favorable (52.7% versus 41.8%) with less unknown cases (29% versus 41.4%) but without significant difference (Table 5).

The most common system affected by the ADRs in our study (PV-MTCP) was skin and appendage (24.2%). Also in 2 studies from Thailand and Malaysia, skin and appendage system was the most affected (48.9 and 49.5%) [17, 18]. In an Indian study, the majority of the patients (53%) had gastrointestinal reactions [14]. In 2 studies from Nepal and Iran [15, 19], the most common system affected by the ADRs was liver and biliary system (58.5 and 37%).

The principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, and chronic hepatitis B and C infections [20]. There are several strategies to prevent the occurrence of these ADRs. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of anti-TB chemotherapy [20]. It is also recommended that liver function should be studied every two weeks during ATT to prevent serious hepatotoxicity [21]. A few guidelines were also published mentioning the management of hepatotoxicity due to anti-TB drugs [22, 23]. It is also the responsibility of the health care professionals to counsel the patients regarding the early signs of hepatotoxicity.

For minimizing risk of serious ADRs, the MPVC collaborating with some hepatologists and phthisiologists developed a practical procedure of TB hepatotoxicity that helps prescribers to manage the risks associated with anti-TB drugs.

Adverse drug reactions to certain drugs may differ within each country, reflecting different patterns of prescription, socioeconomic status, and culture.

On December 31, 2013, 18 international signals have been generated with combined anti-TB form (ERIP-K4). Among these 18 signals, 11 were from Morocco including 3 critical signals: hepatitis, cholestatic hepatitis, and peripheral neuropathy. Three signals had a Moroccan score of IC025 higher than international score of IC025: arthralgia, pruritus, and peripheral oedema, testifying to the importance of these three signals (Table 6).

All these Moroccan signals are known except peripheral edema including lower limb edema which is a new signal not documented in the literature.

Therefore, a technical committee of pharmacovigilance met in July 2013 to discuss these signals. Recommendations were issued for increased vigilance of these signals especially lower limb edema requiring more laboratory investigations to rule out other causes of the occurrence of edema. The committee decided also to initiate a study to evaluate the relationship of accountability of this significant lower limb edema.

Limitations. The strong point of our study is the collection of all major and minor ADRs, but the limitation is the absence of files of patients who have not developed ADRs for estimating the incidence of ADRs.

5. Conclusion

The integration of pharmacovigilance in the Moroccan Tuberculosis Control Program has increased spontaneous reporting of all TB ADRs, decreased severity of ADRs, allowed a procedure of anti-TB drugs induced-hepatotoxicity and detected of new signals of anti-TB drugs.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

Moroccan Pharmacovigilance Center acknowledges the efforts of all phthisiologists who contributed to this work in particular Professor Iraqi Ghali, Director of University Hospital Moulay Youssef in Rabat. The authors expressed their gratitude also to the Global Fund support and the Direction of Epidemiology and Lung Diseases support.

References

  1. J. Perriot, É. Chambonnet, and A. Eschalier, “Les effets indésirables des antituberculeux; prise en charge,” Revue des Maladies Respiratoires, vol. 28, no. 4, pp. 542–555, 2011. View at: Publisher Site | Google Scholar
  2. E. Bloss, L. Kukša, T. H. Holtz et al., “Adverse events related to multidrug-resistant tuberculosis treatment, Latvia, 2000–2004,” International Journal of Tuberculosis and Lung Disease, vol. 14, no. 3, pp. 275–281, 2010. View at: Google Scholar
  3. N. Awofeso, “Anti-tuberculosis medication side-effects constitute major factor for poor adherence to tuberculosis treatment,” Bulletin of the World Health Organization, vol. 86, no. 3, pp. B–D, 2008. View at: Google Scholar
  4. J. Berg, E. J. Blumberg, C. L. Sipan et al., “Somatic complaints and isoniazid (INH) side effects in Latino adolescents with latent tuberculosis infection (LTBI),” Patient Education and Counseling, vol. 52, no. 1, pp. 31–39, 2004. View at: Publisher Site | Google Scholar
  5. http://srvweb.sante.gov.ma/Documents/BE%20edition%20complet.pdf.
  6. http://portfolio.theglobalfund.org/en/Grant/Index/MOR-011-G05-T.
  7. R. H. B. Meyboom and R. J. Royer, “Echelle d’Imputabilité dans les Centres de Pharmacovigilance de la Communauté Européenne,” Pharmacoepidemiology and Drug Safety, vol. 1, pp. 87–97, 1992. View at: Google Scholar
  8. https://adr.who-umc.org/.
  9. https://tools.who-umc.org/webroot/.
  10. S. Puavilai and P. Timpatanapong, “Prospective study of cutaneous drug reactions,” Journal of the Medical Association of Thailand, vol. 72, no. 3, pp. 167–171, 1989. View at: Google Scholar
  11. K. Wilson, “Sex-related differences in drug dispostion in man,” Clinical Pharmacokinetics, vol. 9, no. 3, pp. 189–202, 1984. View at: Google Scholar
  12. L. P. Ormerod and N. Horsfield, “Frequency and type of reactions to antituberculosis drugs: observations in routine treatment,” Tubercle and Lung Disease, vol. 77, no. 1, pp. 37–42, 1996. View at: Publisher Site | Google Scholar
  13. D. Yee, C. Valiquette, M. Pelletier, I. Parisien, I. Rocher, and D. Menzies, “Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis,” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 11, pp. 1472–1477, 2003. View at: Publisher Site | Google Scholar
  14. V. K. Dhingra, S. Rajpal, N. Aggarwal, J. K. Aggarwal, K. Shadab, and S. K. Jain, “Adverse drug reactions observed during DOTS,” Journal of Communicable Diseases, vol. 36, no. 4, pp. 251–259, 2004. View at: Google Scholar
  15. P. V. Kishore, S. Palaian, P. Ojha, and P. R. Shankar, “Pattern of adverse drug reactions experienced by tuberculosis patients in a tertiary care teaching hospital in Western Nepal,” Pakistan Journal of Pharmaceutical Sciences, vol. 21, no. 1, pp. 51–56, 2008. View at: Google Scholar
  16. F. Zakham, “Direct sequencing for rapid detection of multidrug resistant Mycobacterium tuberculosis strains in Morocco,” Journal of Infection and Drug Resistance, vol. 6, pp. 207–213, 2013. View at: Google Scholar
  17. W. Suwankesawong, Use of Thaivigibase to Assess the Safety of Anti-Tuberculosis Drugs for Thai Patients: Application from Thai Vigibase, Health Product Vigilance Center, Food and Drug Administration, Ministry of Public Health, 2011.
  18. F. Kurniawati, “Adverse drug reactions of primary anti-tuberculosis drugs among tuberculosis patients treated in chest clinic,” International Journal of Pharmaceutical and Life Sciences, vol. 3, no. 1, pp. 1331–1338, 2012. View at: Google Scholar
  19. K. Gholami, E. Kamali, M. Hajiabdolbaghi, and G. Shalviri, “Evaluation of anti-tuberculosis induced adverse reactions in hospitalized patients,” Pharmacy Practice, vol. 4, no. 3, pp. 134–138, 2006. View at: Google Scholar
  20. W. W. Yew and C. C. Leung, “Antituberculosis drugs and hepatotoxicity,” Respirology, vol. 11, no. 6, pp. 699–707, 2006. View at: Publisher Site | Google Scholar
  21. M. Wada, “The adverse reactions of anti-tuberculosis drugs and its management,” Nippon rinsho. Japanese journal of clinical medicine, vol. 56, no. 12, pp. 3091–3095, 1998. View at: Google Scholar
  22. K. Tahaoglu, G. Atac, T. Sevim et al., “The management of anti-tuberculosis drug induced hepatotoxicity,” International Journal of Tuberculosis and Lung Disease, vol. 5, pp. 65–69, 2001. View at: Google Scholar
  23. A. Tostmann, M. J. Boeree, R. E. Aarnoutse, W. C. M. De Lange, A. J. A. M. Van Der Ven, and R. Dekhuijzen, “Antituberculosis drug-induced hepatotoxicity: concise up-to-date review,” Journal of Gastroenterology and Hepatology, vol. 23, no. 2, pp. 192–202, 2008. View at: Publisher Site | Google Scholar

Copyright © 2014 Driss Soussi Tanani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views2295
Downloads759
Citations

Related articles