Epidemiology of Leprosy in Vietnam and the Effectiveness of Multidrug Therapy (MDT) in the Management of the Disease

Leprosy is a chronic infection caused by the acid-fast, rod-shaped bacillus Mycobacterium leprae . Leprosy can be considered connected diseases that primar-ily affect the superficial tissues, especially the skin and peripheral nerves. The social and psychological effects of leprosy, as well as its highly visible debilities and sequelae, have resulted in a historical stigma associated with leprosy. Vietnam has seen a highly significant decrease in the prevalence rate (PR) of leprosy since 1983. From 1983 onwards, with the introduction of multidrug therapy (MDT), the prevalence of the disease has dropped to less than one case per 10,000 individuals from 1995. After over two decades, a total of 109 cases were registered with a prevalence rate of 0.01 per 10,000 population in 2017. It is clear that over the past 35 years, the profile of leprosy in Vietnam has been changed significantly followed by the treatment with MDT. Leprosy has become a rare disease in Vietnam. This chapter presents the trend in the epidemiology of leprosy in Vietnam from 1983 to 2018 and also mentions the effectiveness of multidrug therapy (MDT) in the management of this disease. Based on individual records and annual reports, the prevalence of registered cases, the number of new cases detected yearly, their sex, age, classification (MB, multibacillary; PB, paucibacillary) and disability status are carefully presented.


Introduction
Vietnam, officially the Socialist Republic of Vietnam, is the easternmost country on the Indochina Peninsula which is a part of the Western Pacific Region. With another four countries, including China, Malaysia, Papua New Guinea and the Philippines, Vietnam contributed to 86% of the total prevalence, according to the WHO's report in 2010 [1]. While the lack of knowledge about leprosy in the lower socio-economic group is an important cause why most of patients with untreated leprosy end up with severe deformities and disfigurements, there has been a degree of stagnation and new approaches in leprosy control. Therefore, in 1991, the global leprosy control network was established. The WHO set the goal of elimination of leprosy as a public health problem in which the prevalence rate needs to be below one case per 10,000 people [2]. Vietnam has achieved the national target in 1995 and succeeded in maintaining the elimination threshold, reaching that sub-nation at the end of the year 2000 [3]. However, based on the annual data collected from 2000 onwards, several new case detections have been reported [3,4]. This requires continuing the implementation of the main principles of leprosy control in the nation, with a special focus on the five fields, such as timely detection of new cases, contact investigation, multidrug therapy (MDT) treatment, the treatment compliance and prevention of disabilities and also rehabilitation. The strategic directions are integration, early diagnosis and treatment which help to strengthen and sustain leprosy activities, quality patient care and reduction of the leprosy burden of physical, social and economic consequences. The introduction of MDT for the treatment of leprosy in 1983 was one of the important landmarks in combating the disease. In the past, many clinical trials of MDT have been implemented with high effectiveness and well toleration. The addition of ofloxacin to multidrug regimens has been developed to reduce the required duration of MDT possible. Moderate to marked clinical and bacterial improvement with minimal adverse effects has been observed [5,6].

Network of leprosy control programme
Vietnam's National Leprosy Control Programme was established in 1982 [7]. The present national framework for leprosy control is characterized by the integrated delivery of basic leprosy services, which are provided at the peripheral level. The leprosy control system is a part of the healthcare system which follows the administrative system (Figure 1). The National Hospital of Dermatology and Venereology (NHDV) is the leading institute responsible to the Ministry of Health (MOH) for skin diseases, sexually transmitted infections (STIs) and leprosy control in the  whole country [4]. There are the supported systems, namely, Dermato-Venereology Clinic, vertically under NHDV in each province, covering these fields at provincial level. Dermato-venereological activities including leprology work are continuously separated into the leprosy programmes at district level. At the district's social diseases unit in endemic zones, several practitioners are specially trained to work exclusively in leprosy field, whereas in less endemic district, they are in charge of some contagious diseases, including leprosy, tuberculosis, malaria, HIV/AIDS, etc. In each commune that includes 2-5 villages with 1000-3000 people, leprosy and other social diseases are managed by one or two health workers. They are the specialized units with leprosy expertise at intermediate levels that provide the necessary technical guidance. Their main work is to refer suspect cases for diagnosis confirmation, to treat and to follow up confirmed cases. Antileprosy drugs are stored at any levels, from central to local. The leprosy programme plays a paramount importance to facilitate early case detection and reduce the disease burden further in all endemic areas because they encourage voluntary or self-reporting and help increase the capabilities of the peripheral general healthcare staff through training.

Before 1975
There is no exact data of this period because dermato-venereology profession network was just established in 1975, but the estimated prevalence rate of leprosy was 6-7/10,000 population in 1975 [4]. Most of patients are being congregated in places such as leprosy villages/colonies despite no segregation law.

From 1976 to 2018
The National Leprosy Control Programme (NLCP) was formed in 1982, and MDT was implemented 1 year later, in 1983 [7].

The trend in prevalence rate of leprosy
According to the annual data reported from 1983 to 2018, there was a decreasing trend in both prevalence rate and the annual newly detected cases (Figure 2). As a result of the long-term efforts, Vietnam, which was one of the first 15 countries in the region, had reached the goal of elimination at the national level in 1995 with the prevalence rate of 0.7 per 10,000 population [2]. At the end of the year 2000, the subnational target has been reported. In 2000, only 28 provinces reached Vietnam's 3 elimination criteria [3,4]. But from 2001 to 2015, all the rest 36 provinces completed the WHO's elimination goal at the provincial level in the country (Vietnam's 4 elimination criteria) [7], and relatively high case detection rate was found in some area, particularly in the central highland and some southern provinces.
They were varied from 38,652 prevalent cases in 1983, corresponding a rate of 6.78 per 10,000 people, to 18,418 cases, corresponding of 2.71 in 1991 (see Table 1). During this period, the registered prevalence number was very high due to several main factors, such as retreated with MDT in patients previously treated with dapsone and managing the national leprosy by using 24-month regimen without ofloxacin. However, since 1992 onwards, the number of registered prevalence cases reduced dramatically (Figure 2). Starting from 9245 cases in 1992, it decreased to 96 in 2018 and the rate dropped continuously from 1.36 to 0.01 per 10,000 population in the same period ( Table 1). The main reasons were considered, such as disseminating MDT therapy in the whole country and introducing patients to 12-month regimen for shortening the required duration of MDT possible in 1998.
Analysis of a total data from 1983 to 2018 revealed that the prevalence rate has dropped significantly from 6.78 per 10,000 in 1983 to 0.01 per 10,000 in 2018 ( Table 1). It is clear that over the past 35 years, the prevalence rate of leprosy has changed dramatically by around 99.9%. With this prevalence rate, it was believed that the transmission of M. leprae would be reduced and leprosy would naturally disappear. The post-elimination challenges in the future are sustaining high-quality leprosy programmes and reaching the target of district level. Although leprosy has become a rare disease in Vietnam, all activities of the NLCP are sustained from the national to grassroot levels. At the present, Vietnam has several provinces which achieved the goal of elimination at the district level.

Trend in case detection
The new cases include patients who are newly diagnosed during the calendar year. Due to the development of the leprosy network and acceleration of activities of health education, the number of new cases detected yearly was remarkably increased from 1991 to 1997 (Figure 2). A total of more than 32 special projects, namely, SAPEL, LEC and mini-LEC, were conducted in this period, during 1991-1997 [3]. The results, not only the new case detections but also the remaining undetected cases, especially in the high plateau areas and some places in southern provinces, were found out. During 1993-1998 the number of new cases detected annually increased. From 1999 up to now, the annual detection rate has declined (Figure 2). Only 77 cases were detected in 2018 with a rate of 0.1 per 100,000 inhabitants and a decrease from 1795 cases in 1999, corresponding to a rate of 2.35 per 100,000 population ( Table 1). Compared with other countries in the region, Vietnam has significantly declined in the incidence cases. Between 2013 and 2014, while India alone accounted for 58.85% of the global Leprosy burden, with a total of 127,000 new cases detected, that number in Vietnam was only 521 new cases [8], <243.7 times. Because case detection is highly influenced by the intensity of  programme activities, such as service coverage, community awareness and the reporting system as well as sensitivity and specificity of diagnosis, the new case detection rate may not represent the true incidence and the degree of transmission of infection in the community.

Grade 2 disability proportion among new cases
Leprosy usually affects the skin and peripheral nerves. Visible disability, expressed as grade 2 disabilities, may be noted as the results of involvement damage of certain peripheral nerves [6,7]. The proportion of grade 2 disabilities among new cases from 1983 to 2018 fluctuated a lot depending on the trend in case detection (see Figure 3). The highest rate was 40.82% in 1983 then decreased to 17.86% in 1993 ( Table 2). The main cause may be related to shortening of timely diagnosis and treatment of cases, before nerve damage has occurred. Ensuring good treatment compliance of patients also led to reduce the visible disability rate. This decline reflected the efficacy of leprosy control activities. The grade 2 disability proportion between 1994 and 1997 increased related to the intensive case-finding efforts that were carried out in this period. The projects including LECs, mini-LECs and SAPEL have detected a large number of backlog cases, most of whom could suffer severe deformities and disfigurements as a result of delayed diagnosis. Additionally, some of old patients re-registered as new cases especially those with disabilities that also contributed to increasing the grade 2 disability proportion among new cases. On the other side, the high stigma and low awareness about the disease in the society  have contributed to the delay in case detection that affected high grade 2 disability proportion. Fortunately, the rate decreased again and reached a level of 18.75% in 2018 ( Table 2). It requires that the healthcare system conduct retraining courses on leprosy at provincial, district and communal levels to sustain the effectiveness of the network of leprosy control programme for self-reporting and early treatment.

Female and children among new cases
The age-old stigma associated with the disease remains at least hundreds of years ago in Vietnam. The impact of stigmata attached to leprosy had effect not only on male but also on female and children [7]. Because of the fear of infecting the family members and being divorced, leprosy women were forced to be infertilized and kept themselves aloof. In the past, the children who were born by parental leprosy were not allowed to attend or study with other "normal" children. Table 3 shows that the distribution of sex and age leprosy patients among new cases was not stable. The proportion of female leprosy detected from 1983 to 2018 was around 19.8-38% (Figure 4). This is convenient with other previous studies in some countries in the region such as Thailand, India and Myanmar [1,2,[8][9][10][11][12].
Here the reported rate of children among new case detection decreased from 169 in 1983 to under 10 cases since 2014 ( Table 3). From 9.57% in 2000, there is no case observed in 2018 (Figure 4). This is a good signal and could be related to success in completing the subnational target at the end of the year 2000 in Vietnam. Some tests have been conducted to make prognosis in high-risk children group, such as gelatin particle agglutination test (GPAT). This measurement tool helped dermatologists to easily assess the transmission of the disease in the community. Tran Hau Khang et al. reported that children with GPAT positive at high titer of more than 1:64 and whose mother/father is a leprosy patient can be considered as the highest risk group developing the disease [13]. As a result, GPAT has proven its important role in early detection of leprosy in children. This could partially explain why the decrease of transmission of the disease led to the reduction in the proportion of children among new cases.

Multibacillary (MB) among new cases
The proportion of MB leprosy among new cases is an important indicator of the magnitude of a potential source of transmission and risk for complications including reactions and neuritis that could lead to disabilities when not treated adequately. In Vietnam, there was the gradual elevation of MB patient rate among newly detected cases from 40.1% in 1983 to 47.2% in 1993. However, from 1994 onwards, the proportion increased significantly. More than 90% (92.71% in 2018) of new case detection were MB patients ( Table 3). This could be explained by some factor, such as change in the criteria for classification and in the clinical presentations to some extent. Further studies in various countries in the long term are necessary to determine the relation between the operational and the epidemiological factors that are contributing to the increase in MB proportion.

Special leprosy projects
In order to enhance knowledge about leprosy which increases misconceptions about the disease's transmission and treatment and to widen case-finding activities in certain areas, several special projects were carried out, such as SAPEL, LECs, mini-LECs and health educational campaigns. A total of 32 activities were implemented from 1991 to 1997 covering over 3 million inhabitants. It comprised 8 LEC projects (1,100,200 populations), 6 SAPEL activities (872,000 individuals) and 18 other activities (1,030,000 people). The number of new cases detected was reported corresponding to these projects: 603, 154 and 663 cases [3,7]. The total number of newly detected cases in 7 years (1991)(1992)(1993)(1994)(1995)(1996)(1997) was 1420 related to these activities, corresponding to 7% out of total new cases in this period (20,282 cases). This reflected the effectiveness of the network of leprosy control programme. Besides that, the support of the Pacific Leprosy Foundation (PLF) as a partner member and the coordination meetings about leprosy activities that were held with government and local nongovernmental organizations (NGOs) assisted the strengthening of the national leprosy programmes in Vietnam. This ensured programme sustainability by promoting integration within the general health system and also emphasized the need for building and maintaining effective partnerships to improve quality leprosy services and reduce further the disease burden due to leprosy.

Effectiveness of MDT in management of leprosy
Leprosy is a long-lasting infection caused by bacteria that can be eliminated by antibiotics. Early diagnosis and treatment of cases can prevent or minimize the onset of further disabilities related to complications, including reactions and neuritis [5,6,[14][15][16][17]. MDT implementation began in 1985 in the Western Pacific Region. It reached 10% coverage in 1988. By 1994, almost 100% MDT coverage was reached [1,2,9,14]. Development and implementation of MDT was the most important achievement in the history of leprosy control in which the introduction of a single-dose treatment regimen for single lesion and 1 year duration for MB leprosy has contributed a great benefit to leprosy patients by shortening of the required duration of MDT. One of the most essential components of the leprosy programme is also ensuring that all new patients who start MDT complete the full course of treatment within the prescribed period of time. A completed treatment patient means that a PB leprosy patient completes 6 monthly doses of PB-MDT adverse side effects were observed, including itch, erythema and vomit, all of which resolved quickly within 2-3 days. Only 1.7% developed erythroderma and required hospitalization [5,6,[15][16][17]. With these results, ofloxacin has proven to be a powerful bactericidal drug against M. leprae. The introduction of MDT therapy containing Ofloxacin reduced the prevalence rate down to under 0.5% since 1998.
High rate of MB leprosy treatment completion was reported. Nearly 24,000 patients implemented MDT with the completion rate of 100% from 2013 to 2018 (112/112 detected cases treated with MDT in 2017, 77/77 in 2018) (see Tables 1  and 4). It coincided with a continuous decline in the prevalence rate (see Figures 2  and 5). These results represent the effectiveness of expending efforts of healthcare system form national to grassroot levels. With the financial aid of the government, NGOs and WHO, leprosy patients are treated free of charge with MDT at their own home and can pursue a job suitable to their health. There is lack of data of relapse case during the conduct of MDT therapy from 2000 until now and therefore, the effectiveness of MDT in the management of leprosy in Vietnam over the recent 18 years could not exactly be concluded.

Conclusions
With the introduction of MDT in 1983 and the efficacy of leprosy programme activities, the epidemiology of leprosy in Vietnam has dramatically improved. Leprosy is becoming a part of skin neglected tropical diseases (NTDs), a diverse group of communicable diseases that prevail in tropical and subtropical countries, particularly in the easternmost country, Vietnam. At present, leprosy is one of 20 diseases formally recognized as NTDs worldwide. However, three out of five main strategies given to combat NTDs are particularly for leprosy. This means that even though leprosy is considered to be eliminated, the health system including the Ministry of Health and the leading institute, NHDV, in Vietnam are still focusing on sustaining quality leprosy services. Nowadays, majority of the patients are now able