TREATMENT Leprosy ANTIMICROBIAL THERAPY Active Agents
Established agents used to treat leprosy include dapsone (50–100 mg/d), clofazimine (50–100 mg/d, 100 mg three times weekly, or 300 mg monthly), and rifampin (600 mg daily or monthly); see “Choice of Regimens,” below. Of these drugs, only rifampin is bactericidal. The sulfones (folate antagonists), the foremost of which is dapsone, were the first antimicrobial agents found to be effective for the treatment of leprosy and are still the mainstays of therapy. With sulfone treatment, skin lesions resolve and numbers of viable bacilli in the skin are reduced. Although primarily bacteriostatic, dapsone monotherapy results in a resistance-related relapse rate of only 2.5%. When dapsone monotherapy was discontinued in lepromatous patients treated for ≥18 years who had been smear-negative for several years, relapses began to occur in the first year after cessation and occurred in ~1% annually thereafter during the next nine years (total, 10%). Dapsone is generally safe and inexpensive. Individuals with glucose-6-phosphate dehydrogenase deficiency who are treated with dapsone may develop severe hemolysis; those without this deficiency also have reduced red cell survival and a hemoglobin decrease averaging 1 g/dL. Dapsone’s usefulness is limited occasionally by allergic dermatitis and rarely by the sulfone syndrome (including high fever, anemia, exfoliative dermatitis, and a mononucleosis-type blood picture). When rifampin has been included in finite regimens to treat multibacillary leprosy (including World Health Organization [WHO] multidrug therapy), several studies have documented double-digit relapse rates, particularly frequently in patients with a high BI. Relapses following the discontinuation of rifampin-containing regimens (unlike those following the discontinuation of dapsone monotherapy) generally begin only after 6 years and most commonly occur after >10 years. It must be remembered that rifampin induces microsomal enzymes, necessitating increased doses of medications such as glucocorticoids and oral birth control regimens. Clofazimine is often cosmetically unacceptable to light-skinned leprosy patients because it causes a red-black skin discoloration that accumulates, particularly in lesional areas, and makes the patient’s diagnosis obvious to members of the community.
Other antimicrobial agents active against M. leprae in animal models and at the usual daily doses used in clinical trials include ethionamide/prothionamide; the aminoglycosides streptomycin, kanamycin, and amikacin (but not gentamicin or tobramycin); minocycline; clarithromycin; and several fluoroquinolones, particularly ofloxacin and moxifloxacin. After rifampin, the most bactericidal agents against M. leprae in mice and patients appear to be minocycline, clarithromycin, and ofloxacin, but these drugs have not been used extensively in leprosy control programs. Most recently, rifapentine and moxifloxacin have been found to be especially potent against M. leprae in mice. In a clinical trial in lepromatous leprosy, moxifloxacin was profoundly bactericidal, matched in potency only by rifampin.
Choice of Regimens Antimicrobial therapy for leprosy should be individualized, depending on the clinical/pathologic form of the disease encountered. Tuberculoid leprosy, which is associated with a low bacterial burden and a protective cellular immune response, is the easiest form to treat and can be cured reliably with a finite course of chemotherapy. In contrast, lepromatous leprosy may have a higher bacillary load than any other human bacterial disease, and the absence of a salutary T cell repertoire requires prolonged or even lifelong chemotherapy. Therefore, careful classification of disease prior to therapy is important.
A reasoned approach to the treatment of leprosy is confounded by several issues:
Even without therapy, TT leprosy may heal spontaneously, and dapsone monotherapy is generally curative.
In tuberculoid disease, it is common for no bacilli to be found in the skin prior to therapy. Thus there is no objective measure of therapeutic success. Furthermore, despite adequate treatment, TT and particularly BT lesions often resolve minimally or incompletely, while relapse and late type 1 lepra reactions can be difficult to distinguish.
LL leprosy patients commonly harbor viable M. leprae “persisters” that are the source of relapse if therapy is discontinued. Because leprosy may relapse many years after cessation of antibiotic therapy, prolonged follow-up after completion of treatment is recommended in order to prevent further disability and deformity.
Even though primary dapsone resistance is exceedingly rare and multidrug therapy is generally recommended (at least for lepromatous leprosy), there is a paucity of information from experimental animals and clinical trials on the optimal combination of antimicrobial agents, dosing schedule, and duration of therapy.
In 1982, the WHO made recommendations for leprosy chemotherapy administered in control programs. These recommendations recognized the limited resources available for leprosy care in the very areas where it is most prevalent and the frustration and discouragement of patients and program managers with the previous requirement for lifelong therapy for many leprosy patients. Thus, for the first time, and without supporting clinical-trial evidence (particularly data on long-term relapse frequency), the WHO advocated a finite duration of therapy for all forms of leprosy and—given the prohibitive cost of daily rifampin treatment in developing countries—encouraged the monthly administration of this agent as part of a multidrug regimen. The WHO treatment regimens were specifically meant for control programs where implementation of a finite regimen for all forms of leprosy would substantially decrease the operational burden of leprosy care; these regimens were not claimed to be optimal in locales where more considerable resources are available. Over the ensuing years, however, the WHO recommendations have been broadly implemented worldwide. For treatment purposes, the WHO originally classified patients with few bacteria in the dermis (BI <2) as paucibacillary and those with many bacteria (BI >2) as multibacillary. The WHO recommended that paucibacillary leprosy in adults be treated with 100 mg of dapsone daily and 600 mg of rifampin monthly (supervised) for 6 months (Table 174-2). As an alternative for patients with single-lesion paucibacillary leprosy, the WHO recommended a single dose of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg). The recommendation for multibacillary leprosy in adults was 100 mg of dapsone plus 50 mg of clofazimine daily (unsupervised) and with 600 mg of rifampin plus 300 mg of clofazimine monthly (supervised). Originally, the WHO recommended that lepromatous patients be treated for 2 years or until smears became negative (generally in ~5 years). In subsequent years, the WHO mandated several modifications to their original multidrug-treatment recommendation, primarily related to leprosy classification criteria and treatment duration (see “The Leprosy Elimination Campaign: Modifications of the Multidrug Regimen and Their Consequences,” below).
Several factors have caused many authorities to question the WHO recommendations and to favor a more intensive approach. Among these factors are—for multibacillary patients—a high (double-digit) relapse rate in several locales (reaching 20–40% in one locale, with the rate directly related to the initial bacterial burden) and—for paucibacillary patients—demonstrable lesional activity for years in fully half of patients after the completion of therapy. The more intensive approach (Table 174-2) calls for tuberculoid leprosy to be treated with dapsone (100 mg/d) for 5 years and for lepromatous leprosy to be treated with rifampin (600 mg/d) for 3 years and with dapsone (100 mg/d) throughout life.
With effective antimicrobial therapy, new skin lesions as well as signs and symptoms of peripheral neuropathy cease appearing. Nodules and plaques of lepromatous leprosy noticeably flatten in 1–2 months and resolve in one or a few years, while tuberculoid skin lesions may disappear, ameliorate, or remain relatively unchanged. Although the peripheral neuropathy of leprosy may improve somewhat in the first few months of therapy, rarely is it significantly alleviated by treatment.
Although two of the three recommended drugs (dapsone and clofazimine) are only bacteriostatic against M. leprae, and although bactericidal agents have been identified since the WHO formulated its recommendations, significant studies employing the available alternatives in newly designed regimens have not been initiated. Given that moxifloxacin, like rifampin, is profoundly bactericidal in leprosy patients and that short-course chemotherapy for tuberculosis is possible only when two or more bactericidal agents are used, a moxifloxacin/rifamycin-based regimen including either minocycline or clarithromycin (each more potent than either dapsone or clofazimine) appears promising; such a regimen may prove to be more reliably curative than WHO-recommended multidrug therapy for lepromatous leprosy and may allow a considerably shorter course of treatment.
THE LEPROSY ELIMINATION CAMPAIGN: MODIFICATIONS OF THE MULTIDRUG REGIMEN AND THEIR CONSEQUENCES The World Health Assembly resolution of 1991 proposed to “eliminate leprosy as a public health problem” in all countries by the year 2000, with success defined as <1 in 10,000 persons with leprosy not having completed a course of multidrug therapy. When leprosy elimination appeared not to be occurring in that time frame, several changes were made to WHO multidrug therapy recommendations to simplify leprosy diagnosis and treatment, ease operational requirements for control programs, and facilitate attainment of the elimination target:
The duration of treatment of multibacillary leprosy was reduced from 2 years to 1 year in 1995 and to only 6 months in 2002. Neither duration was supported by prior clinical trials, and neither has been demonstrated in trials with prolonged follow-up to provide a reliable cure. However, this reduction in duration of therapy for multibacillary leprosy had the effect of reducing for elimination purposes the number of multibacillary cases by a factor of four.
The recommendation for multibacillary treatment was first changed to mandate therapy for any patient whose skin smear was positive. By 1995, skin biopsies and even skin smears were no longer advocated for leprosy diagnosis and classification. For treatment purposes, classification henceforth was to be determined on clinical grounds alone: more than five anesthetic skin lesions or enlarged nerves were to be considered multibacillary and fewer lesions paucibacillary. Unfortunately, such classification often led to under-treatment for some patients and over-treatment for others. Although leprosy often can be diagnosed on clinical grounds alone, it is not infrequently confused with other dermatologic disorders, and the diagnosis not uncommonly remains uncertain even for seasoned leprologists. Skin smears and biopsies often clarify a leprosy diagnosis and earmark those patients most prone to relapse after the completion of therapy. With these diagnostic tests abandoned, leprosy diagnosis has been profoundly compromised.
The WHO advocated the integration of leprosy into national general health services. In most countries where leprosy is endemic, those services are already overburdened, and the prospects that their leprosy patients will receive optimal care is most unlikely. Unfortunately, in endemic countries, medical education often ignores leprosy. Therefore, in general health services, a leprosy diagnosis is frequently delayed or missed, and a rise in leprosy disability and deformity has consequently been encountered worldwide.
The WHO now promotes “accompanied multidrug therapy,” which allows a newly diagnosed patient—if accompanied by a companion who will offer assistance and encourage drug compliance—to receive the full complement of the leprosy regimen at the time of diagnosis; thereafter, the patient is no longer counted as a case and often is no longer entitled to receive further leprosy services. Accompanied multidrug treatment entirely eliminated directly observed therapy—a cornerstone of effective treatment for tuberculosis—from the leprosy treatment regimen. Like that for all chronic diseases, including tuberculosis, compliance with leprosy treatment has proved consistently unreliable. Compliance was previously ameliorated to some extent by the directly observed monthly component of the WHO leprosy regimen.
The WHO now encourages “uniform multidrug therapy,” whereby all leprosy patients receive the same 6 months of treatment previously reserved for multibacillary cases. This treatment duration for multibacillary cases (or an even longer duration) has not proved reliable in preventing relapse. Moreover, patients whose cases were previously classified as paucibacillary receive clofazimine—a drug whose use is not necessary and is often cosmetically and psychosocially unacceptable, marking patients with a leprosy diagnosis.
Since 1995, the WHO went on record as not advocating for patient follow-up after completion of multidrug treatment. Thus, relapse is assuredly underreported, and its impact is not appreciated.
A by-product of the elimination campaign and the public perception that leprosy elimination is at hand is the substantial diminution of funding for both patient care and research. An older generation of leprologists is retiring, specialized leprosy facilities are disappearing, and recruitment of professionals for careers as leprosy clinicians and researchers has been substantially reduced. As a consequence, leprosy research has been largely abandoned. In particular, though there are real prospects for improving chemotherapy for leprosy and evaluating new antimicrobial agents both in mice and in clinical trials, almost no such efforts have commenced in the past decade. Furthermore, the mouse footpad laboratories required for such work worldwide are few and lack the capacity to monitor those efforts.
THERAPY FOR REACTIONS Type 1 Type 1 lepra reactions are best treated with glucocorticoids (e.g., prednisone, initially at doses of 40–60 mg/d). As inflammation subsides, the glucocorticoid dose can be tapered, but steroid therapy must be continued for at least 3–6 months lest recurrence supervene. Because of the myriad toxicities of prolonged glucocorticoid therapy, the indications for its initiation are strictly limited to lesions whose intense inflammation poses a threat of ulceration; lesions at cosmetically important sites, such as the face; and cases in which neuritis is present. Mild to moderate lepra reactions that do not meet these criteria should be tolerated, with glucocorticoid treatment withheld. Thalidomide is ineffective against type 1 lepra reactions. Clofazimine (200–300 mg/d) is of questionable benefit but in any event is far less efficacious than glucocorticoids.
Type 2 Treatment of ENL must be individualized. If ENL is mild (i.e., if it occurs without fever or other organ involvement and with occasional crops of only a few skin papules), it may be treated with antipyretics alone. However, in cases with many skin lesions, fever, malaise, and other tissue involvement, brief courses (1–2 weeks) of glucocorticoid treatment (initially 40–60 mg/d) are often effective. With or without therapy, individual inflamed papules last for <1 week. Successful therapy is defined by the cessation of skin lesion development and the disappearance of other systemic signs and symptoms. If, despite two courses of glucocorticoid therapy, ENL appears to be recurring and persisting, treatment with thalidomide (100–300 mg nightly) should be initiated, with the dose depending on the initial severity of the reaction. Because even a single dose of thalidomide administered early in pregnancy may result in severe birth defects, including phocomelia, the use of this drug in the United States for the treatment of fertile female patients is tightly regulated and requires informed consent, prior pregnancy testing, and maintenance of birth control measures. Although the mechanism of thalidomide’s dramatic action against ENL is not entirely clear, the drug’s efficacy is probably attributable to its reduction of TNF levels and IgM synthesis and its slowing of polymorphonuclear leukocyte migration. After the reaction is controlled, lower doses of thalidomide (50–200 mg nightly) are effective in preventing relapses of ENL. Clofazimine in high doses (300 mg nightly) has some efficacy against ENL, but its use permits only a modest reduction of the glucocorticoid dose necessary for ENL control.
Lucio’s Phenomenon Neither glucocorticoids nor thalidomide is effective against this syndrome. Optimal wound care and therapy for bacteremia are indicated. Ulcers tend to be chronic and heal poorly. In severe cases, exchange transfusion may prove useful.