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1. DIFFERENT REGIMES IN
LEPROSY
PRESENTER- DR AJAY KUMAR SAINI
MODERATOR : DR NAUSHIN AARA MA’AM

2. Introduction: History
Pre – Antibiotic Era
• Chaulmoogra oil / Hydnocarpus oil
• Obtained from the fruit ( seed) of a tree native to coastal
regions ( ghats ) of South East Asia( India and Burma)
• It use was 1st formally described by Mouat (1854)
• Used with camphorated oil (with added resorcin)
• Orally, injection and topical
• Response was inconsistent ( LL)

3. Evolution of treatment regimens in Leprosy
S.N
O
REGIMEN DISEASE
TYPE
YEAR DURATION
1 DDS monotherapy MB
PB
1950s to
1980
Lifelong (continous)
10 year
2 WHO – MDT (21 days intensive therapy ) MB 1981 24 mts or till SSS is – ve
3 WHO – MDT PB 1981 6 mts (daily)
4 WHO-MDT (Modified by IAL and NLEP
TO 14 Days intensive therapy)
MB 1983 24 mts or till sss is -ve
5 WHO – MDT (FDT 24) MB 1994 24 mts (daily)
6 WHO – MDT ( FDT – 12) MB 1997 12 mts (daily)
7 RO( continuous treatment for 28 days) PB/MB 28 days daily
8 ROM – 6 PB 6 mts (monthly)
9 ROM -12 MB 12 mts (monthly)
10 ROM - 1 SSLPB 1997 1 day (single dose)
11 PMMx - 1 MB 1 day (single dose)

4. The Sulphone Monotherapy Era
The introduction of effective antimicrobial treatment for
leprosy, first with the sulphones was done by Faget in 1941
• Initially promin and solapsone, intravenous injectable
sulphones, were utilised.
• Used by Chochrane in india in 1946.
• Lowe and smith used oral diaminodiphenylsulphone(DDS) in
1949.
• Monotherapy with dapsone became the standard of care
throughout the world in 1950s
• Daily dose of 1-2 mg/kg body weight
• Clinical improvement seen in 3-6 month.

5. • In 1962 clofazimine was confirmed to be effective in
treatment of leprosy.
• In 1964 first confirmed case of dapsone resistance
• In 1970 rees et al demonstrated rifampicin as the most potent
bactericidal drug against leprosy
• In 1972 shepard suggested combined use of rifampicin and
acedapsone

6. Factor responsible for development of mdt-
• Drug resistance
• Bacterial persistence
• Defaulting
• Reduce post treatment relapse
• Reduce side effect
• Increase Cost effectiveness

7. MDT ( WHO)
• In 1981, WHO recommended a classification for operational
purpose as pauci- and multi-bacillary leprosy (PB and MB)
 BI> +2 at any site is MB leprosy
 BI up to +2 is PB leprosy
 In current classification any patient with 6 or more lesion is
MB leprosy
• in 1981 WHO recommended treatment with more then one
drug for 24 months or till smear negative for MB leprosy
• For 6 months in PB leprosy

8. • In 1990 NLEP introduced 24 months fixed MDT in modified MDT
district programs.
• In 1994 WHO recommended fixed period of 24 month for MB
leprosy.
 MB patient should complete 24 monthly doses within 36 months
period
 PB patient 6 monthly doses within 9 months period
• WHO recommended that patient receive their drugs in monthly
calendar blister packs.
• In 1997 WHO and NLEP recommended FDT ,MDT 12 months for MB
Leprosy and MDT 6 months for PB leprosy.

9. • WHO reported high relapse rate in patient with BI more then
4+
• NLEP of india “in training manual for medical officers ,2009”
put a foot note stating “rarely, specialists may consider
treating a person with high BI for more than 12 months
;decision is based on clinical and bacteriological evidence.”

12. Need for new Drugs and Regimens
1. Duration of treatment is too long
2. Dapsone and Clofazimine are only weakly bactericidal
against M. leprae, results in long duration of treatment
and low compliance rate.
3. Daily dosing of Dapsone and Clofazimine cannot be
supervised.
4. Some patients cannot tolerate any of the drugs in MDT.

13. Newer chemotherapeutic agents for Leprosy
1 Fluoroquinolones Ofloxacin, Pefloxacin, Sparfloxacin,
Temafloxacin, Moxifloxacin and
Sitafloxacin
2 Tetracyclines Minocycline
3 Macrolides Clarithromycin
4 Ansamycins Rifabutin, Rifapentin, R- 76-1
5 Dihydrofolate
reductase inhibitors
Brodimoprim and K- 130
6 Fusidic acid
7 Beta lactam
antibiotics

14. Fluoroquinolones
• Act by inhibiting the alpha sub unit of the enzyme DNA gyrase
Ofloxacin
• 400 mg is Bactericidal against M leprae (less than a single dose of
rifamicin)
• 28 daily doses killed 99.99 % 0f viable m leprae(grosset et al 1990)
• Use in treatment of patient with MB leprosy who can not take
rifampicin/ resistant to rifampicin.
• Treatment of patient with MB leprosy who refuse to take
clofazimine
Ji B,Perane EG, Petinon C, et al. Clinical trial of ofloxacin alone and in combination with dapsone and
clofazimine for the treatment of lepromatous leprosy, Antimicrob Ag Chemother 1994;38:662-667

15. Macrolides
• It acts by linking to the 50s sub-unit, thus inhibiting bacterial
protein synthesis
• Clarithromycin appears the most promising
• Potent bactericidal against m. leprae but less than rifampicin
• When administered in a dosage of 500mg daily to leprosy
patients, the drug killed 99% of M leprae by 28 days, and
99.9% by 56 days.
Jacobson RR. Needed research in the chemotherapy of leprosy related to the individual
patient, Int J Lepr, 1996; 64 Suppl:S16-S 20.

16. minocycline
• It inhibits protein synthesis by binding to the 30S subunit of
the ribosome.
• its lipophilicity permits it to penetrate the bacterial wall
• The drug is bactericidal against M leprae
• The clearance of viable M leprae from the skin by minocycline
was faster than that reported for CLF and DDS but slower than
that for RMP .
• With dose of 100 mg daily 99% and 99.99% of the viable m.
leprae killed by 28 and 56 days of treatment respectively.
• Lesser reactions especially in lepromatous cases

17. Research trials
1. Rifampicin with ofloxacin trials
• Continuous treatment of 28 days in MB and PB leprosy.
• Double blind multicenter trial co-coordinated by WHO was
undertaken in which MB smear positive patients (BI >2+)
recruited
• Equally divided into four different group
1. MDT 12 doses
2. MDT 12 doses + ofloxacin for 28 days
3. Rifampicin + ofloxacin for 28 days
4. MDT 24 doses
• After 5 year of follow up in the group treated with RO for 1
month indicating high relapse rate.

18. • In “open trial” conducted by BLP in MB smear positive
patients it was observed that RO group was associated with
far more risk of relapse than WHO MB MDT.
• Balagon et al. conducted a trial in PB leprosy patient of 28
days daily dose of RO with 5 month of placebo showed slightly
high relapse rate compared to standard WHO regimes .

19. 2.ROM TRIAL( SINGLE DOSE THERAPY)
• Based on laboratory and clinical studies ,WHO 7th expert
committee(1997) recommended the use of single dose of
rifampicin(600mg) ofloxacin(400mg) minocycline (100mg) for
single skin lesion PB Leprosy.
• Multicentric double blind RCT trials was conducted in india by
WHO.
• Follow up duration was 18 month
• Study showed that ROM is almost as effective as the standard
WHO PB MDT in the treatment of single lesion PB leprosy.

20. 3. ROM(SINGLE DOSE) TRIALS
• For smear negative two to three skin lesion without nerve
trunk involvement
• Significant difference was present in favor of WHO MDT in
term of relapse rates.
• It can be alternative treatment regimens for PB leprosy
patient with 2 to 5 lesion but careful follow up for relapse is
necessary.

21. 4.ROM TRIAL( INTERMITTENT THERAPY)
• short term objective –
 to study clinical response and any side effect and reaction
which might occur during and after the end of treatment.
 to make chemotherapy of leprosy simpler and operationally
feasible for mass programs.
 to ensure better treatment compliance.
• Only two studies have been reported using multiple doses of
ROM in lepromatous leprosy (LL). One in the Philippines by
Villahermosa et al another in brazil.

22. • Comparing patients with BL and LL Who were given either
monthly ROM or the standard MDT for 24 months
• In both study both groups had a similar fall in BI after 24
months of treatment and similar clinical and histological
improvements
• In the Philippines study the BI continued to fall after the
completion of antibiotic treatment and no relapses were
recorded during the subsequent 64 months after treatment

23. Uniform MDT ( U – MDT)
• Uniform leprosy treatment that would not require disease
classification
• Therapy given for 6 months period
• Assess the treatment response in term of relapse rate
• Rifampicin 600 mg/mt, Dapsone 100 mg daily and clofazimine
at 50 mg/day and 300 mg/mt
• Advantage
– Shortens the course of treatment
– Increases patient adherence to treatment
– Improves the performance of health workers in the field

24. • Evidence from experimental studies suggests that 2–3 months’ MDT is
capable of killing almost all viable bacilli in the mouse footpad model
(Ji et al. 1996a; Banerjee et al. 1997).
• An experimental study further suggests that the rifampicin-resistant
mutants in an untreated lepromatous patient are likely to be eliminated
by 3 months’ daily treatment with dapsone–clofazimine combination
and by that time rifampicin with three monthly doses would have killed
over 99.999% of the viable Mycobacterium leprae (Ji et al. 1996a).
• Loss of infectivity of M. leprae after only 1 month of WHO MB– MDT or
with a single dose of rifampicin was documented (Ji et al. 1996b)

25. • WHO study in china and india in 2008 showed U-MDT
appears promising with Respect to clinical status of skin lesion
• Study by rao et al in india showed MDT for 6 months was
effective in PB leprosy but was too short regimen for MB
leprosy
• Penna et al study in brazil (2012) showed that high BI (BI>+3)
and UMDT had high incidence of first reaction and recurrent
reaction during follow up of 1 year

26. Accompanied MDT
• WHO recommended that certain patients provided their full
course of MDT at the time of diagnosis’
• User friendly
• Suitable for mobile population ,patient living in remote areas
and in areas of civil strife.
• Operational study in india showed that treatment adherence
is more in AMDT compare to routine MDT .
• Monitoring of self administration dapsone – by urine spot test

27. Moxifloxacin based Regimens
• Most powerful bactericidal agent against M. leprae
• Synthetic broad spectrum antibiotic with inhibition of the
DNA gyrase.
• Preliminary observations on 54 patients in Mumbai 2009
• (Rifampicin 600 mg + moxifloxacin 400 mg + minocycline 200
mg)/ month
• 6 months for smear negative
• 12 months for smear positive

28. • Results
– Remarkable clinical regression within 2 – 3 months in
all cases
– No major S/E seen with drugs
– Mild ENL was noticed in one patient and type 1
reaction in another patient
• Still long term observations are needed to draw any
conclusions

29. Quadruple regimen
• In a study at Belgium, MB patients were given weekly
supervised doses of rifampicin, ofloxacin, clofazimine, and
minocycline for 6 weeks
• Initial results are highly encouraging. Relepse rate was only
2%
• However, long-term follow-up is needed in all these
shortened regimens

30. Other Regimens for special situations(WHO)
1.who refuse to accept clofazimine
• In 1993 WHO advocated daily ofloxacin 400 mg or
minocycline 100 mg as substitutes for clofazimine
or
• Monthly ROM for 24 months

31. 2.Allergy or inter-current disease such as chronic
hepatitis or Severe dapsone toxicity
PB cases Dapsone should be stopped
Clofazimine sustituted for
dapsone for a period of 6 months
MB cases Dapsone should be stopped
No further modification is required

32. 3. Infected with rifampicin - resistant M. leprae
• Commonly also resistant to dapsone
• In these cases their treatment depends almost entirely on
clofazimine
• Clofazimine in combination with ofloxacin and minocycline is
most effective
PB cases (50 mg of clofazimine + 400 mg of ofloxacin + 100
mg minocycline or 500 mg of clarithromycin) daily
for 6 months
MB cases Daily administration of 50 mg clofazimine with 400
mg ofloxacin and 100 mg of minocycline or 500mg
of clarithromycin for 6 months
followed by
Daily administration of 50 mg clofazimine together
with 400 mg of ofloxacin or 100 mg of minocycline
For 18 months

33. Role of immunotherapy
problem existing after chemotherapy
– Persisters
– Long duration of treatment
– Occurance of reaction and nerve damage
– Relapses
– Large pool of dead bacilli
• Immunomodulators with chemotherapy that can stimulate
CMI have been applied to reduce those problem of
chemotherapy alone.

34. • These agents can be divided into three broad
categories:
1. Drugs such as levamisole and zinc
Levamisole – immunomodulatory effect on defective T
lymphocyte function
-increase in EAC rosette counts
zinc- inhibit complement dependent immune complex
formation and neutrophil chemotaxis.
2. Antigenically related mycobacteria such as BCG, ICRC
bacillus, BCG plus killed M. leprae, Mycobacterium w
(Mw), and M. vaccae.
3. Other immunomodulators such as transfer factor,
recombinant interferon γ (IFN γ), and interleukin-2.

35. Conclusion
• The evolution of WHO MDT treatment regimens is main tool
and strategy for the control of disease.
• Time duration of treatment of MB leprosy is still in debate
with increase cases of relapse and persisters.
• Future hope lies in combination therapy of MDT and other
newer regimens and immunotherapy .

36. THANK YOU