**10. Management**

#### **10.1. Medical treatment**

MDT is the key point of disease control. Dapsone, rifampicin and clofazimine are the first line drugs. Because of the increased drug resistance due to monotherapy and the ineffectiveness of each one on *M. leprae*, the use of multiple drugs was initiated in 1981 in line with WHO's recommendation. The use of dapsone, rifampin, and clofazimine (MB-MDT) is recommended for MB leprosy (BB, BL, LL), while dapsone and rifampin (PB-MDT) is recommended for TL, BT for 6 months since 1982. However, the duration of treatment for MB leprosy has changed over the years. The use of 12 months of MDT independent of smear is currently recommended, although formerly it was suggested that the treatment be continued until two consecutive negative skin smears are obtained [78, 79]. A single dose combination of rifampin 600 mg, ofloxacin 400 mg and minocycline 100 mg is recommended for patients with low baseline leprosy with a single lesion [80, 81]. Recommended doses are presented in **Table 1**.

Minocycline, clarithromycin and ofloxacin can be used as second-line drugs in MDT, where first-line drugs cannot be tolerated. Minocycline 100 mg/Daily can be used instead of dapsone and clofazimine, ofloxacin 400 mg/day instead of clofazimine, clarithromycin 500 mg/daily can be used where dapsone, clofazimine or rifampin cannot be tolerated [82].

**WHO recommended treatment regimens**

**Agent**

**Dose** *Tuberculoid (TT and BT)(paucibacillary)*

Adult

Dapsone Rifampicin

> Childᵜ

Dapsone Rifampicin

450 *Lepromatous (LL, BL, BB) (multibacillary)*

Adult

Dapsone Rifampicin Clofazimine

> Childᵟ

Dapsone Rifampicin Clofazimine ᵜAdjust dose appropriately for child less than 10

ᵟAdjust dose appropriately for child less than 10

given twice a week, and clofazimine 100

**Table 1.**

Recommended treatment doses of leprosy.

years. For example, dapsone 25

years. For example, dapsone 25

mg given once a month under supervision.

mg daily, rifampicin 300

mg daily and rifampicin 300

mg given once a month under supervision.

mg given once a month under supervision, clofazimine, 50

 mg

An Update on the Epidemiology, Diagnosis and Treatment of Leprosy

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49

50

mg/daily and 150

mg/a month

450

mg/a month

50

mg/ daily

50

mg/daily and 300

mg/a month

600

mg/a month

100

mg/daily

12 months

Dapsone Rifampicin Clofazimine

Dapsone Rifampicin Clofazimine

1

mg/kg/daily

10–20

mg/kg/daily (not >600)

1

mg/kg/daily

50

mg /daily

600

mg/daily

100

mg /daily

24 months

mg/a month

50

mg /daily

600

mg/a month

100

mg/daily

6 months

Dapsone Rifampicin

Dapsone Rifampicin

10–20 *Lepromatous (LL, BL, BB) (multibacillary)*

mg/kg/daily (not >600)

1

mg/ kg/daily

600

mg/daily

100

mg/daily

12 months

**Duration**

**Agent**

**Dose** *Tuberculoid (TT and BT) (paucibacillary)*

**Duration**

**NHDP recommended treatment regimens**

WHO recommends that cases with a skin smear test +, or those without a definite diagnosis, are definitely treated with MB-MDT. Furthermore, attention should be paid to the fact that MB leprosy cases should not be treated with PB-MDT [81].

On the other hand, the National Hansen's Disease Programs (NHDP)—in the USA—involves different regimen. Treatment is recommended 12 months for PB leprosy and 24 months for MB leprosy. Furthermore, unlike the current regimen of WHO, rifampin is used daily rather than monthly [82]. Recommended doses are presented in **Table 1**.


glycolipid-1)-the only accessible test-is increasing day by day [67]. Search for effective diag

nostic tests is accelerated by shifting the focus of the leprosy control strategy to early diag

should take prophylaxis among these individuals.

48 Hansen's Disease - The Forgotten and Neglected Disease

**10. Management**

**10.1. Medical treatment**

doses are presented in **Table**

**1** .

MB leprosy cases should not be treated with PB-MDT [81].

monthly [82]. Recommended doses are presented in **Table**

nostic and rapid treatment. Several studies have shown a correlation between serological titer and BI. The skin smear, the gold standard for classification, is thought to be a test that can be used as a support for clinical findings when histology is not possible [73, 74]. There was also a relationship between serology and reaction and relapse risk. Patients with a high PGL-1 Ig M level had a high risk of developing type 1 reactions [75]. In another study, posttreatment reactions were found to be more likely to develop in patients with positive serology after treatment [76]. In another important meta-analysis, seropositive healthy contacts were observed to develop three times more leprosy when compared to negatives [77]. In the light of these findings; additional studies are needed to determine serology, classification, early diagnosis, follow-up of disease, detection of individuals at risk, and determination of who

MDT is the key point of disease control. Dapsone, rifampicin and clofazimine are the first line drugs. Because of the increased drug resistance due to monotherapy and the inef

fectiveness of each one on *M. leprae*, the use of multiple drugs was initiated in 1981 in line with WHO's recommendation. The use of dapsone, rifampin, and clofazimine (MB-MDT) is recommended for MB leprosy (BB, BL, LL), while dapsone and rifampin (PB-MDT) is recommended for TL, BT for 6 months since 1982. However, the duration of treatment for MB leprosy has changed over the years. The use of 12 months of MDT independent of smear is currently recommended, although formerly it was suggested that the treatment be continued until two consecutive negative skin smears are obtained [78, 79]. A single dose combination of rifampin 600 mg, ofloxacin 400 mg and minocycline 100 mg is recom

mended for patients with low baseline leprosy with a single lesion [80, 81]. Recommended

Minocycline, clarithromycin and ofloxacin can be used as second-line drugs in MDT, where first-line drugs cannot be tolerated. Minocycline 100 mg/Daily can be used instead of dapsone and clofazimine, ofloxacin 400 mg/day instead of clofazimine, clarithromycin 500 mg/daily

WHO recommends that cases with a skin smear test +, or those without a definite diagnosis, are definitely treated with MB-MDT. Furthermore, attention should be paid to the fact that

On the other hand, the National Hansen's Disease Programs (NHDP)—in the USA—involves different regimen. Treatment is recommended 12 months for PB leprosy and 24 months for MB leprosy. Furthermore, unlike the current regimen of WHO, rifampin is used daily rather than

> **1** .

can be used where dapsone, clofazimine or rifampin cannot be tolerated [82].





ᵟAdjust dose appropriately for child less than 10 years. For example, dapsone 25 mg daily, rifampicin 300 mg given once a month under supervision, clofazimine, 50given twice a week, and clofazimine 100 mg given once a month under supervision.

**Table 1.** Recommended treatment doses of leprosy. Moxifloxacin, pefloxacin, sparfloxacin, levofloxacin, and rifapentine that is a rifampin derivate are other agents with demonstrated efficacy [83, 84]. Clinical trials are needed in the long term.

train family members or nearby people for observation purposes [81]. On the other hand, the NHDP recommends first follow-up on 1st month and then with 3 months periods. Reaction therapy should be followed up closely. Disease progression is largely due to incompatibility to treatment. Complete information about possible reactions, complications, drug side effects should be provided and the patient and his/her relatives compliance to treatment should be ensured. At each follow-up, laboratory tests for drug toxicity are recommended with full clinical evaluation including nerve examination. While complete blood, urea, creatinine, AST, ALT follow up is adequate, it is advisable to check glucose 6 phosphate dehydrogenase level for once for dapsone usage before treatment, if possible. A yearly skin smear or biopsy is recommended to follow the bacteria burden. After treatment, it is advisable to follow up at

An Update on the Epidemiology, Diagnosis and Treatment of Leprosy

http://dx.doi.org/10.5772/intechopen.80557

51

Existence of persister strain, insufficient/inappropriate treatment, monotherapy, drug resistance, high BI at diagnosis, number of lesions and lepromin negativity are factors that increase relapse risk. The risk of relapse after MDT has decreased considerably. In a study of 3248 patients followed for 16 years, cumulative relapse rates after MDT were 1.78% [99]. The relapse rate was 6.1/1000 person years in one of the last current studies in which 2177 patients are followed up [100]. To reduce the risk of relapse, individualization of treatment duration is recommended in

Drug resistance is the result of leprosy-resistant transmission (primary resistance) or mutation-induced secondary resistance which develops under treatment [102]. *FolP1, rpoB, and* gyrA gene mutations are associated with dapsone, rifampicin and ofloxacin resistance. Gene sequencing by PCR is a rapid and sensitive method to demonstrate drug resistance [103]. Due to the lack of effective second-line drugs; resistance to first-line drugs is a matter of concern to the WHO Global Leprosy Program. In 2008, drug resistance global surveillance was initiated to assess the efficacy and drug resistance level of the current leprosy control strategy. Eighteen reference centers have been established in 18 pilot countries and mutation detection by PCR has begun. Obtained data suggest that resistant *M. leprae* does not pose a risk for cur-

With MDT, in 1985, with 5.1 million leprosy cases falling to 3.1 million in 1991, WHO aimed to eliminate leprosy worldwide in 2000. Elimination target was 1/10,000. Countries like India and Brazil have been under the target even though the target has been reached substantially around the world. Although Brazil is one of the last countries to reach the goal today, endemic areas like Chhattisgarh, Pará and Madura are still far behind the target. On the other hand, in spite of successful elimination program, WHO declared in 2013 that leprosy control is faltered due to the plateau of the incidence of leprosy until 2005, the new diagnosis of leprosy cases with G2D remain constant between 2010 and 2013, and the number of new cases in children is not decreasing. In addition, late-diagnosis-related disabilityending stigmatization of leprosy patients continued. Epidemiological data showed that the

least 5 years of PB cases and 10 years of MB cases [82, 98].

individuals predicted to be at high risk for relapse [101].

**11.1. Drug resistance**

rent disease management [104, 105].

**12. Elimination/prevention**

Another treatment regimen studied is Uniform-MDT. It is the use for 6 months of dapsone, rifampin and clofazimine for patients with both PB and MB. However, the need for using additional clofazimine in PB patients and whether the treatment will be sufficient in MB patients are important questions present. This treatment is believed to set zero the risk of abduction of MB leprosy patients who received insufficient treatment by introducing a PB group [85]. In a study in which MB leprosy relapse was assessed in particular, relapse was found to be well below the targeted 5-year relapse rate of 5% [86]. Existing studies promises hope although further studies are needed [87, 88].

#### **10.2. Treatment of immunological reactions**

#### *10.2.1. Type 1 reaction*

Supportive therapies such as parol, non-steroidal anti-inflammatory drugs (NSAID), can be administered if there are no neuritis findings such as pain, function, or sensory loss. If nerve involvement is present, prednol 0.5–1 mg/kg/day peros is the first choice treatment. When the reaction is relieved, the dose is slowly reduced so that it remains above the dose of 0.25 mg/kg/day for at least 3–6 months. In ongoing process, dose reduction is continued with careful follow-up of nerve functions [89]. Cyclosporin is another option when steroids are not usable [90, 91]. In a study in which azothioprine was assessed, efficacy in type 1 reaction was not demonstrated [92].

#### *10.2.2. Type 2 reaction*

The incidence of type 2 reaction has decreased after addition of clofazimine to MDT with anti-inflammatory effect [93]. If there is no findings of neuritis, supportive treatment care such as NSAID (aspirin, indomethacin) and paracetamol may be administered. Prednol (0.5–1 mg/ kg/day) is the first choice if neuritis is present. Once the reaction is decreased, the dose should discontinued by reducing the dose in time. However, frequently the reaction relapse during dose reduction. In this case, thalidomide, clofazimine and pentoxifylline can be used as adjuvants. WHO recommends to start by using clofazimine 3 \* 100 mg (300 mg/day) and then reduces to 100 mg/day. It should not be used for type 2 reaction as a single agent and for more than 12 months. Reaction can be rapidly controlled by using thalidomide 300–400 mg/day. Dosage may be reduced to 100 mg/day for extended periods of usage. Since it is teratogenic, attention must be paid to the use in women who has childbearing potential [81]. Pentoxifylline is used as 3 \* 400 mg. In a study that compares the efficacy of clofazimine and pentoxifylline, pentoxifylline effectively reduced the initial severity, while clofazimine showed a slow but sustained effect [94]. Resistant erythema nodosum leprosum cases that treated successfully with methotrexate, infliximab and etanercept have been reported [95–97].

## **11. Follow-up**

WHO aims to follow the patients up monthly by 28-day drug supply. In regions where monthly follow-up is difficult, it is recommended that more than a monthly dose be given and train family members or nearby people for observation purposes [81]. On the other hand, the NHDP recommends first follow-up on 1st month and then with 3 months periods. Reaction therapy should be followed up closely. Disease progression is largely due to incompatibility to treatment. Complete information about possible reactions, complications, drug side effects should be provided and the patient and his/her relatives compliance to treatment should be ensured. At each follow-up, laboratory tests for drug toxicity are recommended with full clinical evaluation including nerve examination. While complete blood, urea, creatinine, AST, ALT follow up is adequate, it is advisable to check glucose 6 phosphate dehydrogenase level for once for dapsone usage before treatment, if possible. A yearly skin smear or biopsy is recommended to follow the bacteria burden. After treatment, it is advisable to follow up at least 5 years of PB cases and 10 years of MB cases [82, 98].

Existence of persister strain, insufficient/inappropriate treatment, monotherapy, drug resistance, high BI at diagnosis, number of lesions and lepromin negativity are factors that increase relapse risk. The risk of relapse after MDT has decreased considerably. In a study of 3248 patients followed for 16 years, cumulative relapse rates after MDT were 1.78% [99]. The relapse rate was 6.1/1000 person years in one of the last current studies in which 2177 patients are followed up [100]. To reduce the risk of relapse, individualization of treatment duration is recommended in individuals predicted to be at high risk for relapse [101].

#### **11.1. Drug resistance**

Moxifloxacin, pefloxacin, sparfloxacin, levofloxacin, and rifapentine that is a rifampin derivate are other agents with demonstrated efficacy [83, 84]. Clinical trials are needed in the long term. Another treatment regimen studied is Uniform-MDT. It is the use for 6 months of dapsone, rifampin and clofazimine for patients with both PB and MB. However, the need for using additional clofazimine in PB patients and whether the treatment will be sufficient in MB patients are important questions present. This treatment is believed to set zero the risk of abduction of MB leprosy patients who received insufficient treatment by introducing a PB group [85]. In a study in which MB leprosy relapse was assessed in particular, relapse was found to be well below the targeted 5-year relapse rate of 5% [86]. Existing studies promises

Supportive therapies such as parol, non-steroidal anti-inflammatory drugs (NSAID), can be administered if there are no neuritis findings such as pain, function, or sensory loss. If nerve involvement is present, prednol 0.5–1 mg/kg/day peros is the first choice treatment. When the reaction is relieved, the dose is slowly reduced so that it remains above the dose of 0.25 mg/kg/day for at least 3–6 months. In ongoing process, dose reduction is continued with careful follow-up of nerve functions [89]. Cyclosporin is another option when steroids are not usable [90, 91]. In a study in which azothioprine was assessed, efficacy in type 1 reaction was not demonstrated [92].

The incidence of type 2 reaction has decreased after addition of clofazimine to MDT with anti-inflammatory effect [93]. If there is no findings of neuritis, supportive treatment care such as NSAID (aspirin, indomethacin) and paracetamol may be administered. Prednol (0.5–1 mg/ kg/day) is the first choice if neuritis is present. Once the reaction is decreased, the dose should discontinued by reducing the dose in time. However, frequently the reaction relapse during dose reduction. In this case, thalidomide, clofazimine and pentoxifylline can be used as adjuvants. WHO recommends to start by using clofazimine 3 \* 100 mg (300 mg/day) and then reduces to 100 mg/day. It should not be used for type 2 reaction as a single agent and for more than 12 months. Reaction can be rapidly controlled by using thalidomide 300–400 mg/day. Dosage may be reduced to 100 mg/day for extended periods of usage. Since it is teratogenic, attention must be paid to the use in women who has childbearing potential [81]. Pentoxifylline is used as 3 \* 400 mg. In a study that compares the efficacy of clofazimine and pentoxifylline, pentoxifylline effectively reduced the initial severity, while clofazimine showed a slow but sustained effect [94]. Resistant erythema nodosum leprosum cases that treated successfully

WHO aims to follow the patients up monthly by 28-day drug supply. In regions where monthly follow-up is difficult, it is recommended that more than a monthly dose be given and

with methotrexate, infliximab and etanercept have been reported [95–97].

hope although further studies are needed [87, 88].

**10.2. Treatment of immunological reactions**

50 Hansen's Disease - The Forgotten and Neglected Disease

*10.2.1. Type 1 reaction*

*10.2.2. Type 2 reaction*

**11. Follow-up**

Drug resistance is the result of leprosy-resistant transmission (primary resistance) or mutation-induced secondary resistance which develops under treatment [102]. *FolP1, rpoB, and* gyrA gene mutations are associated with dapsone, rifampicin and ofloxacin resistance. Gene sequencing by PCR is a rapid and sensitive method to demonstrate drug resistance [103]. Due to the lack of effective second-line drugs; resistance to first-line drugs is a matter of concern to the WHO Global Leprosy Program. In 2008, drug resistance global surveillance was initiated to assess the efficacy and drug resistance level of the current leprosy control strategy. Eighteen reference centers have been established in 18 pilot countries and mutation detection by PCR has begun. Obtained data suggest that resistant *M. leprae* does not pose a risk for current disease management [104, 105].
