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Leprosy, also known as Hansen's disease, is a chronic infective disease caused by acid-fast, gram-positive Mycobacterium leprae (M.leprae). Several modes of transmission are suggested such as skin contact and sexual activities but the primary mechanism is via air by mouth and nasal discharge of untreated infected people. Leprosy can be considered in two parts in which the first milder form involves infection of superficial tissues such as skin. This indeterminate state is usually surmounted by the human body eliciting sufficient immune response, with approximately 95% of people being not susceptible. Nevertheless, if the body produces too high or too low a response, the second more severe form of leprosy develops and progresses leaving deformities in areas such as skin, nervous system, mucosa, limbs and eyes.
Thus, depending on the patient's immune response, leprosy is classified by the World Health Organization (WHO) into multibacillary leprosy in which the body's defense system is ineffective, and paucibacillary leprosy(PB) which produces aggressive response.1 In terms of skin smear tests, MB which has large number of bacteria in skin lesion would produce positive results while PB produces negative results. Another type of classification known as Ridley-Jopling classification divides leprosy into 5 stages; tuberculoid(TT), borderline tuberculoid(BT), midborderline/borderline(BB), borderline lepromatous(BL) and lepromatous(LL) leprosy in which the latter three are the equivalent of MB.
Figure 1: Stages in leprosy infection.4
In 2009, leprosy cases were reported in 121 countries.2 Based on WHO figures, the number of new cases detected in 2008 was 249007 while the registered prevalence of leprosy worldwide at the beginning of 2009 was 213036. Although there has been a steady fall in the number of new cases detected annually, leprosy remains a global threat.
In MB, the first signs and symptoms possibly encountered are numbness, nasal discharge as well as various kinds of lesions, macules, nodules and papules. More severe symptoms may be diffuse skin thickening, eye lesions leading to cataract, secondary infection and nerve lesions.
Although leprosy can affect all people, various specific factors predispose to leprosy. Firstly, leprosy typically affects people living in tropical and subtropical climate such as Africa and South East Asia. People in endemic areas as well as the poor and marginalized community are at greater risk of contracting leprosy. In terms of age, leprosy demonstrates an age-related pattern with peak incidence in children below 10 years old and mid thirties while rarely acquired by infants.3 Besides that, men are generally more susceptible than women and genetic factors may play a role too.
Despite years of incubation period, the differential diagnosis of leprosy is vital because the treatment duration is prolonged. Also, an accurate diagnosis helps in determining the appropriate and effective treatment. In vitro culture of M.leprae is not feasible given the extremely slow growth rate. Methods that can be used include skin lesion biopsy and nasal smears done using Fite's acid fast tissue staining which stains the bacilli red in a blue background or using Hematoxylin and eosin stain (H&E) for histological confirmation.3,4 The number of bacilli visible will denote the type of leprosy. Also, phenolic glycopilid-1 (PGL-1) characteristic of M.leprae can be distinguished using serology techniques.
Given its low mortality rate, leprosy confers debilitating repercussions nevertheless on patients both physiologically and psychologically. Leprosy causes hypoesthesia due to impaired peripheral nerve function, muscle weakness as well as glaucoma, iridocyclitis and inflammation of the eye. As a result, patients are prone to injuries due to diminished vision, and inability to feel and control the body. The incidence of ocular problems is markedly elevated and treatment has proved to reduce prevalence of these complications as described by Gupta et al, whereby 66.3% active leprosy patients manifested ocular problems compared to cured patient at 14.3%.5 If blindness occurs, the relative death risk in blind patients compared to non-blind patients augments by 4.8fold.6 Additionally, leprosy causes clawed fingers and toes, hypopigmented skin lesions with severe ulcerations especially on feet and hands, and facial deformations.
Figure 2: Nerve damage leading to deformity and resultant ulcers and bone resorption.1
Figure 3: A patient with active, untreated MB.1
These disabilities occurs more frequently in MB patients than in PB patients,5,7 and it was suggested that MB patients have higher risk of death compared to PB patients; the average death age being 5 years younger.8 Contrasting prevalence of deformities was concluded in different studies which includes 56.97%,7 82.4%,9 84.4%,10 67%11 and these differences may be the result of improper examination technique or dissimilar grading criteria. However, the point to note here is that all studies acknowledge the severity of this disease.
Also, besides imposing restrictions on physical mobility, such immensely conspicuous debilities have led to a stigma linked to leprosy. Leprosy patients are often subjected to public prejudice and discrimination, leaving them significantly affected both socially and economically. Therefore, accurate diagnosis and aggressive commencement of leprosy treatment is essential to improve patients' quality of life as well as decreasing mortality rate.
2.1 First line therapy
The current pharmacotherapy options include dapsone, rifampicin and clofazimine as the first line therapy. Dapsone is a bacteriostatic antibacterial active against M.leprae. Its good oral bioavailability allows its administration in the tablet form. However, dapsone monotherapy is no longer used as several studies have established profound drug resistance.12,13,14 Following this, WHO recommends the use of three drugs; dapsone, rifampicin and clofazimine, administered as multiple drug therapy (MDT) for MB.1 Supporting this is a systemic evaluation by Kundu et al. which compared dapsone monotherapy to MDT and proved that MDT was significantly superior with capacity to prevent dapsone resistance.15
Figure 4: Multi-drug therapy comprising dapson, rifampicin and clofazimine.2
The current MDT dosing is dapsone 100mg and clofazimine 50mg daily self-administered, and rifampicin 600mg and clofazimine 300mg once monthly supervised. Several studies have shown that MDT is effective in elimination leprosy with low relapse rates.16,17,18,19 For example, Georges et al. demonstrated patients treated on MDT until bacterial clearance showed no validated relapses in the follow up period between 4 months to 5 years and 10 months.16
If adverse effects or contraindication occurs resulting in MDT termination, WHO recommends alternative regimen.20 Nevertheless, it is vital to ascertain conclusively that the negative effects are due to MDT. Dapsone should be terminated immediately if patient develops adverse effects such as Dapsone Hypersensitivity Syndrome (DHS). Rifampicin and clofazimine should be continued at usual dosage. The use of only rifampicin and clofazimine was proven effective for dapsone intolerant patients as described by Sapkota et al.21 These patients treated for a mean duration of 15 months post-dapsone cessation showed steady decrease in mean bacteriological index(BI). Next, if rifampicin is ill-tolerated, alternative therapy comprises clofazimine 50mg, ofloxacin 400mg and minocycline 100mg daily for six months, followed by clofazimine 50mg combined with either ofloxacin 400mg or minocycline 100mg for at least 18 months; given under supervision. Ji et al showed that ofloxacin was capable of eliminating rifampicin-resistant cells.22 Finally if clofazimine has poor acceptability, MDT can be replaced with ROM comprising rifampicin 600mg, ofloxacin 400mg and minocycline 100mg given monthly for 24 months. In a field trial in Senegal, patients on ROM showed satisfactory progress with exceptional compliance possibly attributed to the simpler monthly dosage.23 This combination was further advocated by S. Ura24 and Villahermosa et al25 who compared 2 years ROM treatment with MDT. The studies concluded that both therapy depicted similar advantages regarding their effect on BI, their safety and tolerability. The latter study also showed no relapse after follow ups 5 years later or more.
2.2 Second line therapy
Ofloxacin (a racemic mixture of levofloxacin and dextrofloxacin) and pefloxacin are broad-spectrum flouroquinolones used as second line therapy for MB. They are bactericidal acting via inhibiting enzyme DNA gyrase required in DNA replication thereby interfering with bacterial cell division. Patented in 1982, ofloxacin has been reported to have profound effects on leprosy. A clinical trial executed by Ji et al showed killing of more than 99.99% of viable M.leprae in skin smears inoculated into mouse foot pad, with significant clinical improvements by day 56 of therapy utilizing 400mg ofloxacin daily.26 Also, its effect was not enhanced when used in combination with clofazimine and dapsone. A similar study by Jianping et al which also utilized mice footpad inoculated with leprosy patients' skin biopsies had analogous findings, with no M.leprae growth detected.27 These studies supports the notion that ofloxacin possesses strong bactericidal activity. In another study, Tranquiolino et al reported greater bactericidal activity by pefloxacin and ofloxacin compared to dapsone and clofazimine but not rifampicin.28 This result was later confirmed by Grosset et al which also utilized the fluoroquinolones for treatment during the first two months followed by standard WHO MDT.29 Comparing pefloxacin to ofloxacin, it was found that pefloxacin was less active, requiring 150mg/kg to exert bactericidal effect compared to 50mg/kg for ofloxacin.22 Although minimal side effects were encountered in these studies, the short duration of therapy will not vouch for this as severe adverse reactions have been reported including tendon damage, peripheral neuropathy, cardiovascular toxicity and hepatotoxicity.
Moving on, the broad spectrum minocycline is a tetracycline antibacterial which can be used in patients intolerant to dapsone or clofazimine.30 In a clinical trial by Fajardo et al, patients treated with 100mg daily minocycline for 6 months followed by WHO MDT manifested distinct clinical improvement within the first month with negative PGL-1 antigen at the end of 6 months treatment.31 However, it has been reported that minocycline induce hyperpigmentation which resulted in termination of therapy.32 This side effect ought to be considered particularly when minocycline is used to replace clofazimine. In terms of bactericidal activity, minocycline is considered more effective than clarithromycin, but significantly diminished activity compared to rifampicin.
Clarithromycin is a bactericidal macrolide which suppresses bacterial growth by preventing its protein synthesis. A few clinical trials have shown the advantages of clarithromycin including its capability to kill M.leprae, considerable clinical improvement, patient acceptability and minor adverse effects.33,34 Daily dosage of 500mg revealed killing of 99% bacilli within 28 days and 99.9% by day 56.34 However, limited studies with clarithromycin for leprosy use have been done. Until further researches are carried out, clarithromycin remains the second line treatment for multibacillary leprosy.
Since the past two decades, concerns over established dapsone resistance and increasingly emerging rifampicin resistance have set interest on use of either thioamide or clofazimine concurrently with rifampicin. However, clofazimine was chosen by WHO due to reports of hepatotoxicity when thioamides were used with rifampicin.35,36 Nevertheless, ethionamide and prothionamide are two thioamide drugs being investigated currently as monotherapy for leprosy treatment. Although mainly used for tuberculosis therapy, both drugs have been shown to exhibit significant anti-leprotic activity based on a clinical trial by Fajardo et al.37 Treatment was well tolerated for both drugs with a clinical progress of 74% and 83% respectively. Prothionamide was found to be superior to ethionamide and the overall efficacy of both drugs was similar to that of dapsone and clofazimine. However, they were less efficacious compared to rifampicin, ofloxacin, pefloxacin, minocycline and clarithromycin. They are also more expensive than dapsone. Consequently, thioamides are generally not recommended.
Finally, rifampicin and Isoprodian comprising dapsone, prothionamide and isoniazid were used in Malta Leprosy Eradication Project (MLEP).38 During the 30-year project, the leprosy prevalence steadily declined with exceptionally low degree of relapse and toxicity. It was suggested that treatment with two Isoprodian tablets daily and 600mg rifampicin tablet completely eradicated leprosy from Malta. This may well set the baseline for leprosy treatment. However, Isoprodian being not readily available became a drawback in proceeding with this therapy. Also, the MLEP posed several limitations including the confinement of the project to a relatively small area which hinders its feasibility in larger areas. Additionally, the fact that leprosy was already declining in Malta before the project commenced in 1971 raised questions over the true effect of the therapy on leprosy elimination.
Figure 5: Fall in incidence of leprosy in Malta between 1953 and 2002.38
3.0 Treatment recommendation and supporting evidence
After discussing the treatment options available, 24 months MDT is recommended for the 32 year old female patient in this case study. This decision is made based on the evidences presented previously on efficacy of MDT and also the fact that not many reliable studies have been conducted on other alternatives. The clinical pharmacological principles of each MDT drug and more evidences will be presented in this section to justify the recommendation.
Firstly, dapsone acts via preventing dihyrofolic acid formation thus inhibiting nucleic acid synthesis crucial for M.leprae development. In terms of adverse effects, dapsone has been associated with side effects such as methaemoglobinamia, haemolysis, allergic rhinitis, neurophaty, aganulocytosis and DHS consisting Type 1 reversal reaction and Type 2 erythema nodosum leprosum (ENL) reaction. However, at doses used for leprosy treatment, these side effects are uncommon.39 Besides, DHS can be ameliorated with corticosteroid therapy. In order to curb resistance against dapsone, it should be used concomitantly with rifampicin and clofazimine as MDT due to its established anti-leprotic effect. Also, there has been evidence of significant decline in frequency and seriousness of Type 1 and 2 reactions in patients on MDT, possibly due to rapid arrest on leprosy progression and clofazimine's anti-inflammatory action.20
Next, rifampicin is an antibacterial which plays a major role in inducing rapid M.leprae cell death by inhibiting RNA polymerase involved in protein synthesis. Rifampicin has good oral bioavailability as it is readily absorbed from the gastrointestinal tract. A monthly 600mg dose is highly bactericidal and is almost as effective as rifampicin given daily as subsequent doses do not augment killing rate proportionately. Thus although rifampicin is expensive, a monthly dose contributes to its cost-effectiveness, feasibility and compliance.20 The downside of rifampicin is that adverse effects such as hepatotoxicity have been reported requiring frequent liver function tests and blood tests to detect liver impairment. Other common side effects of rifampicin include gastrointestinal disturbances, fever, headache and rashes. Also, being a liver enzyme inducer, rifampicin upregulates cytochrome P450 resulting in enhanced metabolism of many concomitantly administered hepatic cleared drugs. However, this effect is relatively minimal due to its once monthly dosing. Also, although rifampicin increases dapsone clearance rate, no changes in dose have been necessary as concluded by Pieters et al.40 Interaction with clofazimine is also not likely as rifampicin lack tendency to accumulate in tissues due to its relatively short half life (2-3 hours) compared to clofazimine (70 days).
The third drug used in MDT is clofazimine which based on the MDT dosage is the most well-tolerated amongst the three drugs and is practically non-toxic.41 Clofazimine is a bacteriostatic antibacterial which has predilection towards mycobacterial DNA and inhibits bacterial growth. A 300mg loading dose once monthly serve as a repository to maintain sufficient drug in the body.20 The most common side effect of clofazimine appearing in some 75-100% cases is pink colouration of the skin which are reversible months after stopping therapy.42 Its use is apparent as various studies and clinical trials have proved its efficacy as an anti-leprosy agent without serious adverse effects.43,44,45
In terms of duration of MDT, the recommended duration of MDT has been constantly changing over the years. WHO's previous recommendation of 24 months therapy showed high efficacy with vey low relapse rate. However, in the Seventh Expert Committee (1997), the duration of MDT was shortened to 12 months.1 A study conducted by Sales et al. showed that the decline in bacillary index and occurrence of adverse reactions was analogous for both 12 and 24 months MDT.46 However, this was opposed by US National Hansen Disease Program (NHDP) which stands firm with 24 months MDT with the perspective that more vigorous and longer treatment duration generates higher efficacy with lower relapse rate.30 It also mentioned that the 12 months MDT recommended by WHO was due to cost consideration in developing countries. Based on the BNF, treatment for at least 2 years is necessary for MB.39
The fundamental objective of leprosy therapy is determined by the relapse rate and degree of disability. Having said so, many studies have showed that the relapse rate after completion of MDT for 2 years yielded either zero or very low relapse rate.47,48,49,50,51,52 This is supported by a long term follow-up by Shaw et al47 which proved zero relapse using this regimen and also by a retrospective analysis conducted in China by Shen et al49 which showed that out of 2374 patients followed up for a mean of 8.27 years, five patients had relapse resulting in a relapse rate of 0.21/1000 person-years. Another basis for the 24 months MDT was the review by WHO which revealed a very low relapse rate of 0.9/10 000 person-years in analysis of more than 20,000 MB patients.51 Furthermore, Katoch et al reported that follow up conducted between 12-44 months after MDT treatment revealed deterioration in patients who received only 12-18 months treatment and continuous improvement in those given 24 months therapy.53
Bearing in mind that this patient is a 32 year old female who is at her child bearing age, it is paramount to ascertain is she is pregnant or lactating. Extreme caution should be undertaken if patients are pregnant or lactating, taking into account risks-benefits of leprosy treatment. Several studies have demonstrated adverse effects encountered by pregnant and lactating females such as relapse, type 1 and 2 dapsone reactions and peripheral neuropathy following therapy and are thought to be due to suppression of immunity during pregnancy and breast-feeding.54,55,56 However, some studies have showed that these drugs can be used safely during pregnancy.20,57 Thus, although MDT may incur risks to pregnancy and exacerbate leprosy, a well-organized health plan, frequent and regular supervision may well outweigh the risk with its potential benefits.4,56 Also, effects of MDT on lactating is very minor. Although significant amount of dapsone is found in breast milk, its risks to infants are very minimal. In contrast, the quantity of rifampicin in milk is too small to be harmful to the baby. Likewise, only minute amounts of clofazimine are excreted through breast milk and thus far there have not been reports on severe negative effects on breast-feeding except minor skin discolouration of infant.
All in all, treatment using 24 months MDT has proven highly successful with rapid conversion of disease state from infectious to being non-infectious even after the first dose. MDT remain the ultimate option due to its apparent benefits of curing and stopping transmission of leprosy, its virtually zero relapse rate, minimal side effects, ease of administration and storage, cost-effectiveness and vast clinical evidences. Additionally, patient and public education is vital to aid patient compliance and improve understanding on leprosy. In this context, health professionals carry tremendous responsibilities in giving social support and psychological rehabilitation to help patients cope with the physical and mental distress caused by the disease as well as curing the stigma of leprosy.
Figure 6: A patient with leprosy who was cured using MDT.1