Pharmacovigilance and Moroccan Tuberculosis Public Program: Current Situation

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 (P < 10−3). The average age was 40.7 ± 17.5 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 (P = 10−4), and 40.9% of cases in the first period were serious against 15.8% in second period (P = 0.003). 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.


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 10 5 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 2 Tuberculosis Research and Treatment 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.

Study Design and
Adverse drug reaction is considered a signal if the IC 025 > 0: the probability of observed ADRs is greater than the probability of expected ADRs (IC 025 : Information Component within a range of 95% confidence).

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/10 5 inhabitants) has recorded 927 ADRs (Table 1). 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).   (Table 3). 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).

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 ( < 10 −3 ). 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 lifethreatening (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).

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

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/10 5 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 (<24/10 5 inhabitants) and South Africa is the worst notifier country (191 ADRs) with the high incidence (>300/10 5 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/10 5 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 18.9 ± 20.0 days. Hepatic and neurological ADRs are with almost identical average time (30.5 ± 28.4 and 30.4 ± 36.0 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.
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 Tuberculosis Research and Treatment 5 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. Druginduced 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 IC 025 higher than international score of IC 025 : 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.

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.