Programmatic Addition of Clofazimine to Multidrug Therapy for Paucibacillary Leprosy in India: A One-Size-Fits-All Approach in Absence of Sound Clinical Evidence

ABSTRACT.

In 2024, the Indian National Leprosy Eradication Program released Revised Treatment Guidelines for management of paucibacillary (PB) leprosy, introducing clofazimine into the existing PB multidrug therapy (PB-MDT). This treatment simplification has a dubious scientific basis and serious long-term implications. Notably, this policy shift is derived from WHO guidelines (2018), which issued only a conditional recommendation for uniform-MDT, relying on very low-quality evidence to support the change. We reviewed the studies cited in support and found multiple methodological shortcomings, including insufficient samples, lack of blinding, and unvalidated outcome measures. This significantly undermines the justification for incorporating clofazimine into PB-MDT. Leaving these limitations unaddressed could lead to unintended consequences, including increased drug resistance, higher treatment costs, and adverse drug effects, further complicating disease management. Such a fundamental policy revision should be preceded by rigorous, field-level research, preferably a multicentric, triple-blind superiority trial, alongside establishing surveillance for clofazimine resistance.

INTRODUCTION

The Indian National Leprosy Eradication Program (NLEP) has an annual new case detection rate of 73.26 per 100,000 population,¹ though India operationally achieved elimination in 2005.²

Recently, NLEP Revised Treatment Guidelines (NLEP RTG) for paucibacillary (PB) leprosy were released, adding 300 mg monthly pulses and 50 mg daily doses of clofazimine to PB-multidrug therapy (MDT), making it the same as multibacillary-MDT (MB-MDT) with only a difference in duration (6 versus 12 months).³ This change was purportedly made in keeping with “latest globally accepted scientific research studies and evidence-based practices” to “stop transmission of leprosy and declare a ‘Leprosy Mukt Bharat’ by 2027.”⁴

However, this is not a balanced interpretation of the 2018 WHO Guidelines.⁵ Notably, the WHO Guideline Development Group (WHO-GDG) had only provided a “conditional recommendation, very low-quality evidence” for uniform-MDT (U-MDT) for PB management, not specifically for clofazimine addition to PB-MDT.⁵ We sought to assess and critique the evidence supporting this change in policy.

Critical appraisal of existing body of evidence.

The basis of this recommendation is misinterpreting the answer to the research question posed by WHO-GDG: “Is a single (uniform) treatment regimen for all patients with leprosy as effective and safe as the two currently recommended treatment regimens?” This question aimed to explore if U-MDT (bearing the gifts of simplified treatment without the risk of misclassification and easy programmatic implementation) was safe and effective for PB and, critically, for MB cases.

The WHO-GDG recommended “the same three-drug regimen with rifampicin, dapsone, and clofazimine for all leprosy patients, with a duration of treatment of 6 months for PB leprosy and of 12 months for MB leprosy.” The WHO-GDG clearly stated that this is a conditional recommendation with very low-quality evidence. The methodological concerns in the three India-based studies cited by the WHO-GDG are discussed in Supplemental Table 1.

In addition to the studies cited in the WHO-GDG, let us also discuss the oft-cited^6,7 randomized controlled trial by Katoch et al.⁸ They compared 150 participants receiving 6 months of PB-MDT with 150 participants receiving 6 months of PB-MDT plus 50 mg clofazimine daily (which is different from U-MDT). They reported that persistent active skin patches affected considerably fewer participants in the clofazimine arm (7.5%) than in the PB-MDT arm (16%). At 6 months post-MDT follow-up, the clofazimine arm demonstrated a better response in terms of subsidence of bacterial activity in previously active lesions than the control group (80% versus 30%). However, this study had several methodological limitations—to begin with, the investigators were unblinded after treatment was completed (at 6 months). Hence, there is a strong risk of bias in reporting relapse and reactions. Further, excluding individuals with chronic diseases (diabetes, hypertension) and the elderly limited the study’s generalizability. Sample size adequacy also remained unclear since the authors did not mention which outcome’s incidence difference they wanted to detect with statistical significance. Also, the authors did not report which adverse effects were documented and how their incidences quantitatively differed between the trial arms. Nonresponse rate was not reported. Only per-protocol analysis was reported; no intention-to-treat or sensitivity analysis findings were reported.

However, unlike clofazimine as part of MB-MDT and anti-tubercular treatment, there is limited quality evidence on the safety, efficacy, and cost-effectiveness of adding clofazimine to PB-MDT. Hence, we must proceed with caution, especially because clofazimine is well-documented to cause side effects in MB leprosy and tuberculosis patients. In PB leprosy cases, as well, it can cause skin pigmentation in 10% and xerosis in 30% of PB cases that received MB-MDT.⁹ Rao et al.¹⁰ and Gonçalves et al.⁹ have also reported high rates of adverse effects in PB cases taking these three drugs.

Possible rationale for policy change—is it truly rational?

The following considerations may have motivated NLEP policymakers to add clofazimine to PB-MDT, and we put forth our trepidations.

• “Simplification of treatment logistics”: Because blister packs would be the same for PB- and MB-MDT, it would become much easier to manage and distribute medications effectively. However, we are skeptical regarding health systems implications because, to the best of our knowledge, no study/trial of PB cases given PB-MDT versus MB-MDT for 6 months has yet assessed cost-effectiveness. Adding clofazimine to PB-MDT without sound supportive evidence does not seem prudent, especially in India, where the cost (approximately United States dollar [USD] 6.5 for U-MDT in contrast to USD 1.5 for PB-MDT) would probably be passed on to the patient because there have been significant interruptions in governmental clofazimine supply for treating even MB cases.^11,12

• “Reduced impact of misclassification”: WHO-GDG cited concerns about misclassification when considering U-MDT. The high rate of slit-skin, smear-negative MB cases in India suggests frequent misclassification of PB cases.¹³ If we are truly dealing with a misclassified MB case who gets only 6 months of MB-MDT, there could be serious consequences—difference in treatment duration makes all the difference. Leprosy is a slow and indolent condition—if treatment is left incomplete in an MB case, persisting disease activity, “late reaction” and relapse could be unacceptably high. At a community level, development of rifampicin and/or dapsone drug resistance could further increase, along with clofazimine resistance becoming a looming issue. Over the decades, there have already been major simplifications in classification, with programmatic replacement of Madrid and Ridley-Jopling classifications with the PB/MB binary. This binary, however rational, is ultimately artificial.¹⁴ Some of these efforts made operational sense because they removed programmatic mandates around field-level skin smears in 1982.¹⁵ But oversimplifying treatment to U-MDT does not have strong supportive evidence.

• “Interruption of transmission”: NLEP RTG mentioned that clofazimine has been added with the “hope of interruption transmission” by 2027. However, MB cases predominate in India, comprising 61% of all new cases.^16,17 Additionally, PB cases are not the main transmission source because of a lower Bacteriological Index.¹⁸

• “Potential reduction in resistance”: In 1982, the WHO Study Group recommended MB-MDT to include clofazimine to rifampicin–dapsone as a precaution, stating that a three-drug regimen would prevent persistence/development of rifampicin- or dapsone-resistant strains. Clofazimine was chosen because it was known to be “weakly bactericidal against Mycobacterium leprae” and, up to 1982, “no instances of clofazimine resistance have (sic) yet been proved by mouse inoculation.” For PB cases, they added dapsone to rifampicin to avoid rifampicin resistance in patients who are wrongly diagnosed as PB.¹⁹ Hence, the original motivation behind adding dapsone to PB-MDT was also purely cautionary. Leaping from monotherapy for PB cases to the NLEP RTG of tritherapy is not something the WHO Study Group would have envisioned. Now, MB-MDT has been implemented for almost 5 decades in the absence of anti-mycobacterial routine resistance surveillance. India’s National Guideline for Surveillance of Antimicrobial Resistance in Leprosy 2023²⁰ does not aim to surveil strains resistant to clofazimine, making it unlikely that robust data will be available anytime soon despite four decades of clofazimine usage. Absence of data is not the same as absence of clofazimine resistance itself. A few clofazimine-resistant strains have indeed been reported.²¹ Adding clofazimine to PB-MDT will drastically increase the number of patients receiving a reliable anti-leprotic and second-line anti-tubercular drug before establishing any system to monitor anti-clofazimine resistance emergence. Only a few centers in India can study anti-leprotic drug resistance.^21,22 Capacity building for early resistance detection and response should be prioritized.

• “Decrease in leprosy reactions”: If this is one of the reasons for adding clofazimine to PB-MDT, then most data point in the opposite direction. WHO-GDG reported that relative risk of reactions in PB cases treated with U-MDT versus MB-MDT and PB-MDT were 1.5 (0.77–3.0) and 2.4 (0.11–56) with low strength of evidence.⁵ Hence, there is no significant protection from reactions by adding clofazimine. Poulkar et al.²² also found that adding clofazimine to PB-MDT does not help prevent or improve nerve function impairment.

• “Decrease in relapse rate”: An oft-cited reason is decreased relapse rate when PB cases receive U-MDT. Lack of consensus on criteria for relapse leads to variation in results.^23,24–26 Relapses occur because of adherence issues or are misdiagnosed cases of late reaction—treatment with U-MDT would do nothing for such cases. In a WHO Study of 20,000 MB and 50,000 PB cases in 17 countries (including India), relapse was found to be very low—0.77% for MB and 1.07% for PB 9 years after stopping treatment. Incidence density was 0.23 per 100 person-years at risk (PYAR) for MB and 0.15 per 100 PYAR for PB—relapse density lower than 1.0 per 100 PYAR is considered acceptable.²⁷

RECOMMENDATIONS

Although there are potential benefits to harmonizing PB and MB treatment, adding clofazimine to PB-MDT raises significant concerns. We agree with Ji and Saunderson’s²⁸ critique of the ICMR-NIE trial⁶ (Manickam et al.⁶—a two-drug regimen for PB cases has already shown more than 20 years of effectiveness in preventing relapse, so a trial of U-MDT in PB patients was not a felt need. We also echo Lockwood et al.’s recommendations²⁹ that, before bringing about such a significant nationwide policy change, impartial field-level evidence needs to be generated. We recommend conducting a multicentric, triple-blinded, two-arm superiority trial with PB cases who receive either 6 months of PB-MDT or 6 months of MB-MDT with a 3-year follow-up. The following outcomes should be studied—treatment success rate (with research-grade methods to record clinical, bacteriological, and histopathological lesion changes, validated pain scales used for neuritic pain, and serial ultrasonography scans to monitor neural thickening), 2-year, and 5-year relapse rates. Importantly, a cost-effectiveness (cost per disability-adjusted life year averted) study should be nested within such a trial.

Further, we suggest that the NLEP recommends routine surveillance for clofazimine resistance. This will require increasing the number of centers to detect resistant strains and genetic markers of clofazimine resistance. These may be ambitious endeavors, but for programmatic changes for a population of ∼1.4 billion, the evidentiary basis must be robust rather than speculative.

CONCLUSION

Simplification has been done to great benefit in the past—programmatic replacement of Madrid and Ridley-Jopling classifications with the PB/MB binary (1982), shortening of MB-MDT from 2 years to 1 year, and removing skin smears from the NLEP diagnostic algorithm (1982). These changes made early diagnosis and complete treatment feasible at primary health centers, helping many countries eliminate leprosy.

Notably, at the time of introduction, these changes had been met with vigorous resistance from clinical experts, who are used to making much more nuanced diagnostic and treatment decisions and for whom it may be counterintuitive to “do less” when one can “do more.” Clofazimine addition to PB-MDT is one of those rare occasions when “doing more” is a programmatically recommended strategy, and so it has been met with much less resistance.

However, NLEP policymakers should be mindful of the evidence, which is equivocal at best, and keep in mind the vital principle of quaternary prevention. As public health specialists, we may have gone too far down the road of “lumpers”—it may be wiser to side with the “splitters.” With leprosy statistically eliminated and PB cases being a minor transmission source, the time has come for a more evolved approach to PB leprosy. We must ensure we don’t end up with a nonevidence-based, one-size-fits-all approach to leprosy management.

Note: Supplemental materials appear at www.ajtmh.org.