Therapeutic Response to Thermotherapy in Cutaneous Leishmaniasis Treatment Failures for Sodium Stibogluconate: A Randomized Controlled Proof of Principle Clinical Trial

ABSTRACT

Treatment failure to intralesional sodium stibogluconate (IL-SSG) is a health challenge for cutaneous leishmaniasis (CL) in Sri Lanka. A randomized controlled proof of principle clinical trial, with two arms (viz., radio frequency–induced heat therapy [RFHT] by a ThermoMed™ device (Model 1.8, Thermosurgery Technologies, Inc., Phoenix, AZ) and thermotherapy by a handheld exothermic crystallization thermotherapy for CL [HECT-CL] device) was conducted on 40 CL treatment failures to IL-SSG, from three hospitals in Tangalle, Hambantota, and Anuradhapura, from January 2017 to January 2018, followed up for 180 days post-thermotherapy with a final follow-up in February 2020. Intention-to-treat cure rates were calculated at day 90 (initial cure rate) and at day 180 (final cure rate) posttreatment. Radio frequency–induced heat therapy group: the initial cure rate was 100% (20/20) and the final cure rate was 95% (19/20), with one patient relapsing. The HECT-CL group: both the initial and final cure rates were 80% (16/20), with no relapses and one excluded from the trial. In February 2020 (1.6–3 years posttreatment), 27 traceable patients (RFHT = 16, HECT-CL = 11) remained healed. Second-degree burns were observed with RFHT in 65% (13/20), with HECT-CL in 15% (3/20), which completely resolved subsequently. The cure rates between the two treatment groups were comparable (P = 0.15). Radio frequency–induced heat therapy consumed less time and required only a single hospital visit. Handheld exothermic crystallization thermotherapy for CL is potentially usable at community settings with both being less costly than IL-SSG. This study is the first proof that thermotherapy is an efficacious and safe treatment for CL patients in Sri Lanka, complicated by treatment failure to IL-SSG.

INTRODUCTION

Leishmaniasis is a neglected tropical parasitic disease affecting some of the poorest of countries in the world. As per the WHO’s estimates, about 700,000 to one million new leishmaniasis cases are detected every year.¹ A total of 15,300 laboratory-confirmed cutaneous leishmaniasis (CL) patients were reported island-wide in Sri Lanka from 2001 to 2018, and nearly one-third of the Sri Lankan total population is at risk of acquiring the disease.² Several Leishmania species have been identified as causative agents of leishmaniasis in different parts of the world. Leishmania donovani zymodeme MON-37 causes leishmaniasis in Sri Lanka.³ This Leishmania variant is predominantly dermotropic, and thus, the main clinical form seen in Sri Lanka is CL with only a few visceral cases.^4–7 No other causative species of Leishmania has been identified through several decades of investigations in the local setting.^2–5 The routine treatment for CL in Sri Lanka is intralesional sodium stibogluconate (IL-SSG) injections given weekly.⁸ However, alternative treatment methods such as thermotherapy have also been studied for their safety and efficacy in Sri Lanka as well as in other countries.^9–13 Potential mechanisms of action of heat on leishmaniasis lesions are attributed to heat-induced tissue destruction and up-regulation of the Th1 immune response, which promotes healing.^12,14 A ThermoMed device delivers a controlled heat of 50°C, by using radio frequency waves that induce excessive cell movements. The heat thus generated penetrates evenly through the upper dermis, exposing the amastigotes to the high temperature while not harming the healthy tissue, whereas a handheld exothermic crystallization thermotherapy for CL (HECT-CL) device is a pack containing a saturated sodium acetate solution, calibrated to produce 52 ± 2°C for more than 3 minutes, with a flexible metal disk which when flipped triggers a liquid-to-solid phase exothermic crystallization reaction that releases heat.¹³ Several clinical trials have proven the efficacy and safety of thermotherapy by these devices versus IL-SSG for treatment of newly diagnosed CL patients.^9,10,12,13 Initial cost of the ThermoMed device is between USD 5,000 and 10,000 whereas the HECT-CL device is less than USD 2.^9,15 Both devices are reusable. The ThermoMed device can be recharged, whereas the HECL-CL device can be boiled in water before reuse.

Efficacy of radio frequency–induced heat therapy (RFHT) versus pentavalent antimonials to treat CL caused by L. donovani, Leishmania tropica, Leishmania (V.) braziliensis, Leishmania (V.) guyanensis, Leishmania (V.) panamensis, and Leishmania major has been previously tested in clinical trials in countries such as Sri Lanka, Afghanistan, Colombia, India, and the United States, with results demonstrating the safety and efficacy of RFHT with variable cure rates.^9–12,16,17 The novel, low cost approach of using an HECT-CL device for thermotherapy showed an overall cure rate of 60% and 83% in Peru and Pakistan, respectively.^13,15 However, the interim analysis of another study showed a failure rate of 91% for treatment with HECT-CL.¹⁸

Because a vaccine or prophylactic treatment is not available, chemotherapy remains the mainstay in treatment and control of leishmaniasis. Availability of only a few antileishmanial drugs and emerging treatment failures are major challenges faced by Sri Lanka as well as other countries.^19,20 In a study by Lobo et al.,¹⁴ several patients with CL caused by L. (V) braziliensis with a history of poor response to Glucantime, responded well for RFHT. Although thermotherapy has proven to be effective as a treatment for newly diagnosed CL, to our knowledge, thermotherapy has not been tested in a clinical trial as a cure for treatment failures of CL due to L. donovani. Therefore, the main aim of this study was to determine the efficacy and safety of thermotherapy in CL patients who failed to cure with IL-SSG.

MATERIALS AND METHODS

Trial design.

A randomized controlled proof of principle clinical trial with two interventional arms: 1) RFHT by a ThermoMed device (Model 1.8, Thermosurgery Technologies, Inc., Phoenix, AZ) as a single application at 50°C for a duration of 30 seconds, under local anesthesia with 2% lidocaine (Figure 1A and B)¹⁵ and 2) thermotherapy by an HECT-CL device (Pristech Products, San Antonio, TX), one application daily starting at 52 ± 2°C for 3 minutes in one to three fractions (depending on the pain tolerance of the patient), under anesthesia with a topical anesthetic cream.¹³ Latter treatment was repeated for seven consecutive days (Figure 1C and D]). Overall, 108 patients were assessed for eligibility, of which 68 were excluded and 40 patients were enrolled and randomized to the two arms, in an allocation ratio of 1:1, without masking (Figure 2). A topical antibiotic cream was prescribed posttreatment if signs of secondary bacterial infection were seen. Primary outcome was the cure rate, and the occurrence of second-degree burns and their healing was assessed as a secondary outcome. A data and safety monitoring board provided inputs on the trial design and reviewed interim efficacy and safety data and trial progression.

Figure 1.

Application of thermotherapy by using the ThermoMed device (A and B) and by handheld exothermic crystallization thermotherapy for cutaneous leishmaniasis device (C and D).

Figure 2.

Participant flow summarizing the recruitment and randomization of study participants to the trial and the exclusions (with reasons). n = is the number of patients.

Study participants.

Patients aged between 12 and 65 years, with a skin lesion (localized papule, nodule, ulcer, or plaque with a longest diameter of the lesion less than 5 cm) confirmed as leishmaniasis (through microscopy [×1,000], Olympus CX23, Olympus Corporation, Tokyo, Japan) and those who had failed to cure following a minimum of 10 IL-SSG (Stibovita, Vital Healthcare Pvt. Ltd., Mumbai, India) weekly injections (Figure 3A and B) were recruited as study participants. Those with chronic or concomitant illnesses, with immunocompromised status, who are pregnant, who are breastfeeding, with lesions located on the nose or cartilaginous part of the ear or very close to the eyes and lips or situated within 2 cm distance from a mucous membrane, the participant or the guardian with apparent incapability of to comply with the protocol as judged by the investigator, persons with anticipated unavailability for follow-up visits, persons on pacemakers or those with implanted metallic devices, and those with secondarily infected lesions were excluded from the study.

Figure 3.

(A, B, and C) A CL lesion failed to cure with IL-SSG, on the right ankle, in a 60-year-old man, treated with RFHT by using a ThermoMed device ([A] before thermotherapy, [B] 1 week post-RFHT application, [C] 6 months post-RFHT application). (D, E, and F) A CL lesion failed to cure with IL-SSG, on the left leg, in a 19-year-old woman, treated with thermotherapy by using a HECT-CL device ([D] before thermotherapy, [E] 1 week after completing 7 days of HECT-CL application, [F] 6 months post-HECT-CL application). CL = cutaneous leishmaniasis; HECT-CL = handheld exothermic crystallization thermotherapy for CL; IL-SSG = intralesional sodium stibogluconate; RFHT = radio frequency–induced heat therapy.

Study sites.

Patients were recruited from dermatology clinics in three hospitals, namely, Base Hospital Tangalle (6.02278°N, 80.7975°E) and District General Hospital Hambantota (6.1268°N, 81.126°E) which are in the Southern Province of Sri Lanka and Teaching Hospital Anuradhapura (8.3248°N, 80.4140°E) in North Central Province of Sri Lanka, from January 2017 and followed up at specific time points until 180 days after treatment (viz., on days 14, 30, 60, 90, and 180 posttreatment). A final follow-up for all patients who reached final cure at day 180 was made in February 2020, which was after 1.6, 2, or 3 years posttreatment depending on the date of enrollment to the study.

Case definitions.

Several case definitions were used in this study as follows: 1) “case”: a patient aged between 12 and 65 years with a skin lesion laboratory-confirmed as leishmaniasis which has failed to cure following a minimum of 10 injections of IL-SSG given weekly; 2) “initial cure”: a completely healed lesion with no open ulcer or induration or any signs of inflammation by day 90 posttreatment; 3) “final cure”: cure is sustained with no relapse by day 180 posttreatment; 4) “completely healed”: the lesion has clinically healed (i.e., complete flattening of papules, nodules, or plaques and no open ulcer or induration or any sign of inflammation); and 5) “treatment failure to IL-SSG”: the lesion was not “completely healed” following at least 10 injections of IL-SSG given weekly (with or without other types of treatment).

Twenty patients/arm was taken as the sample size for this proof of principle pilot trial. The 40 patients were allocated to each arm by block randomization with a computer-generated random number series with block sizes four and six, generated through the website www.sealedenvelope.com. Allocation concealment was carried out by placing a paper with the type of treatment mentioned according to the computer-generated random allocation sequence of the treatment, in serially numbered, opaque, sealed envelopes. Random number generation and envelope preparation were carried out before the commencement of the trial by an independent person, who was not involved in the rest of trial procedures. Patients were enrolled on a “first-come first-served basis,” with the envelops opened sequentially and the treatment assigned accordingly for each patient. Blinding was not used in the two devices, and the treatment regimens were clearly different outwardly from one another. Statistical analysis was performed using SPSS 20 (IBM, Armonk, NY). Descriptive statistics was used to analyze clinic–epidemiological data of participants. Intention-to-treat analysis (i.e., including the patients excluded from the trial and who were considered to have had treatment failure) was carried out to calculate the cure rates.

This study was approved by the Ethics Review Committee, Faculty of Medicine, University of Colombo (http://www.med.cmb.ac.lk), Sri Lanka (EC/16/077). Approval for the use of thermotherapy devices was obtained from the National Medicines Regulatory Authority, Sri Lanka (NMRA/CT/07/2016). The trial was registered in the Sri Lanka Clinical Trials Registry (SLCTR/2016/025), and the universal trial number is U1111-1187-5835. Written informed consent was obtained from all trial participants before recruitment.

RESULTS

Baseline demographic and clinical characteristics of the enrolled patients.

All demographic and clinical variables were comparable between the two groups of study participants (Table 1; P-values > 0.05).

Table 1.

Demographic and clinical characteristics of patients treated with thermotherapy by using the ThermoMed device (n = 20) and by the HECT-CL device (n = 20)

Variable	Patients given radio frequency–induced heat therapy by ThermoMed (n = 20)	Patients given thermotherapy by HECT-CL (n = 20)	P-value
Age (years)*	42.6 ± 12.3	39.0 ± 10.8	0.319†
Time duration since onset of the lesion to starting treatment with IL-SSG (months)*	5.4 ± 4.0	6.0 ± 3.3	0.580†
Number of lesions per patient*	1.2 ± 0.4	1.1 ± 0.3	0.643†
Gender‡			0.337§
Male	13 (65.0%)	10 (50%)
Female	7 (35.0%)	10 (50%)
Lesion site‡			0.789§
Head and neck	0 (0%)	0 (0%)
Trunk	2 (10.0%)	2 (10%)
Shoulder and upper limbs	9 (45.0%)	10 (50%)
Lower limbs	8 (40.0%)	8 (40.0%)
More than one site	1 (5.0%)	0 (0%)
Lesion type‡			0.680§
Papule	4/23 (17.4%)	4/22 (18.2%)
Nodule	4/23 (17.4%)	1/22 (4.5%)
Plaque	4/23 (17.4%)	5/22 (22.7%)
Ulcer	11/23 (47.8%)	12/22 (54.5%)
Number of IL-SSG weekly injections*	12.6 ± 5.7	12.3 ± 2.4	0.831†

HECT-CL = handheld exothermic crystallization thermotherapy for CL; IL-SSG = intralesional sodium stibogluconate.

^*Data expressed as “mean ± SD.”

^†Independent sample T test was performed on all discrete variables.

^‡Data expressed as the “number of cases” (percentage with respect to the total number n).

^§Pearson’s chi-squared test was performed on all categorical variables.

Efficacy: RFHT group.

The initial cure rate (at day 90) was 100% (20/20), with one patient getting a relapse by day 180. Therefore, the final cure rate (at day 180) was 95% (19/20). The patient who had a relapse was an 18-year-old female, with a CL nodule on her leg of 3 months duration. The nodule has persisted, despite treatment with 13 IL-SSG weekly injections before being treated with RFHT. The HECT-CL group: one patient defaulted treatment and was excluded from the trial at the treatment phase. Three patients who were not cured by day 90 were taken off the trial at day 90 and referred to the dermatologist for further management with standard CL treatment.⁸ Therefore, the initial cure rate was 80% (16/20). Because there were no relapses, the final cure rate was also 80% (16/20) (Figure 3). The three patients who failed to cure were 1) a 40-year-old woman, with a papule on her arm, 2) a 38-year-old man, with a 2-cm × 2.5-cm CL plaque near the elbow, and 3) a 40-year-old man, who had a papule with a few satellite lesions around it, and who were treated with weekly IL-SSG injections started after 3–4 months following the appearance of the lesions and continued for 13–18 weeks before their recruitment for the study. The cure rates between the two treatment groups were comparable (P-value = 0.15).

Safety: RFHT group.

Thirteen patients (13/20 = 65%) suffered second-degree burns with blistering and rupture of blisters within the first week after treatment.

Handheld exothermic crystallization thermotherapy for CL group.

Majority had only slight erythema and inflammation at the thermotherapy site, although three patients (3/20 = 15%) had second-degree burns. However, as this was expected from data of previous studies, patients were made aware of this possibility before treatment and were closely followed up.¹³ All second-degree burns in both groups completely healed without any complications.

Sustained cure.

The 35 patients (RFHT = 19, HECT-CL = 16) who achieved final cure were seen in February 2020 as a long-term follow-up point for relapses and/or new lesions on any part of the body. Of the 35, eight patients were untraceable to follow-up, although the balance 27 patients (16/19 in RFHT and 11/16 in HETC-CL group) did not have any relapses or new lesions. The post-thermotherapy duration of these 27 patients were 1.6, 2, or 3 years (10/27 = 3 years, 17/27 = 2 years, and 8/27 = 1.6 years).

DISCUSSION

When the two modalities of thermotherapy (viz., RFHT by a ThermoMed device and thermotherapy by an HECT-CL device) used in this study were considered in general terms, the ThermoMed device is costly and it could be administered only where heathcare facilities/personnel are available. In comparison, initial cost of the HECT-CL device is low and may be administered by a minimally trained person even at community level because its application is simple and a topical anesthetic cream could provide sufficient anesthesia before its application.

According to a per patient cost estimation calculated in a previous study in Sri Lanka, 1) in a clinic where 20 people will be treated per week, cost of one time application of thermotherapy by using the ThermoMed device per patient was USD 1.54; and 2) for a course of seven injections of 1 mL of IL-SSG/day, given weekly, per patient cost was USD 11.09.⁹ Although the initial cost of the RFHT device is high, per patient cost is much lower than IL-SSG. Taking the cost of an HECT-CL device as USD 2, where it will be reused for seven consecutive days for application of thermotherapy (with staff and consumable cost of USD 1.2 added), the total cost for one treatment course of 7 days/patient is USD 3.2. The same HECT-CL pack in principle could be reused on other patients, which could reduce the treatment cost further. Thus, thermotherapy will be cheaper than IL-SSG. When an HECT-CL pack is reused (irrespective of whether it will be reused for the same patient or for a different patient), it would be best to clean the surfaces of the pack thoroughly with 70% ethanol, boil in water to restore the liquid state of sodium acetate solution, and let it cool down before reusing. However, the maximum number of cycles the HECT-CL pack may be reused remains to be investigated. Furthermore, because the mechanism of generation of heat in the HECT-CL device is based on a chemical reaction as opposed to radio frequency waves in RFHT, it has the potential to be used for patients for whom RFHT is contraindicated, such as those with pacemakers, although this was not tested in the current study.

From the patients’ point of view on the loss of income or time, RFHT needed only one application and thus required a patient to come to the hospital only once. Depending on the distance from the hospital to the workplace/school/home, the time spent for taking treatment will be a few hours, a half day or a maximum of full day. On the other hand, HECT-CL treatment administered in the hospital clinic needed seven consecutive days of application, and getting 7 days of continuous leave from work or being absent from school was a difficult choice for most patients. Such travel to and fro between their home and hospital also results in a much higher financial, educational, or time-related loss than in the case of RFHT. In case of IL-SSG, the number of weekly visits depends on the patient’s response to the treatment with an average time taken as 10 weeks.²¹ Therefore, when considering the cost of treatment per patient and the loss of income, education, or time of the patient, RFHT is superior to other two types of treatment.

In both devices, the side effects were limited to second-degree burns which healed completely without complications. Similar outcomes have been reported in previous studies.^9,10,13 Such adverse events might be attributed to mishandling of the device or its improper application, although it remains speculative so far. These observations emphasize the need for adequate training of personnel as a prerequisite to adoption of thermotherapy as a routine treatment option. By contrast, treatment with SSG is associated with toxicity and side effects. Although intralesional administration of SSG has lesser side effects than when administered intravenously, the IL-SSG injections are painful, and such repeated injections given over lengthy periods are unacceptable by any standard. Therefore, the use of thermotherapy seems a sensible option from both the health sector’s and patients’ point of view.

Thermotherapy has shown to provoke a protective immune response in the host.¹⁴ In our study, all the 27 patients who were contactable for the long-term follow-up did not have any relapses or new lesions, despite them living in highly endemic areas for CL for 1.6–3 years post-thermotherapy. This is an important observation in our trial, when compared with the findings of a previous study conducted at the Teaching Hospital Anuradhapura in which 3 of 170 (1.2%) CL patients who were treated with IL-SSG relapsed during a 6-month follow-up period after achieving apparent cure.²² However, further investigations are required to define the role of protective immunity following thermotherapy.

The causative agent of CL in Sri Lanka has previously been established as L. donovani through studies conducted over the past two decades.^3,23 Therefore, assumption was made in this study that the isolated parasites were indeed L. donovani, although species identification was not performed using molecular investigations, which may be viewed as a limitation. With almost all trial participants (39/40) being local residents of highly endemic areas for CL and no overseas travel history reported during the preceding 5 years, it could be stated with a reasonable level of certainty that the causative species is likely to be L. donovani. The IL-SSG treatment failure in the study group was based on clinical judgment as per the case definitions. The validity of the use of clinical judgment is supported through findings of longitudinal case studies conducted in the local setting using similar case definitions that have fairly convincingly demonstrated poor treatment response to IL-SSG, despite repeated and prolonged therapy.¹⁹ However, studies are ongoing to confirm drug resistance of local parasites using standard in vitro assays that will further strengthen this argument (authors’ unpublished data). Cutaneous leishmaniasis lesions are generally considered to self-heal eventually, although the duration is not exactly known and the phenomenon remains poorly studied. Therefore, it was not considered to influence the cure rates of the two treatment arms in this study, and because of ethical reasons, no attempts were made to withhold treatment in a third group of patients.

This study is the first proof of the utility of thermotherapy for successful treatment of CL patients in Sri Lanka who have failed to cure with routine therapy of IL-SSG as well as the first proof that the HECT-CL device can be used to treat CL in the local setting. We would also highlight the importance of thorough training of handlers of the devices that may minimize or avoid the second-degree burns observed in both treatment groups. In conclusion, thermotherapy is an efficacious and safe treatment for complicated cases of CL with treatment failure to sodium stibogluconate in Sri Lanka.