Mem Inst Oswaldo Cruz, Rio de Janeiro, 107 (Suppl.I) December 2012
Brazilian clinical trial of uniform multidrug therapy for leprosy patients - the correlation between clinical disease types and adverse effects
ICentro de Referência Dona Libania, Fortaleza, CE, Brasil
IIUniversidade Federal de Goiás, Goiânia, GO, Brasil
IIIFundação Alfredo da Matta, Manaus, AM, Brasil
IVUniversidade Estadual do Ceará, Fortaleza, CE, Brasil
VUniversidade Federal do Ceará, Fortaleza, CE, Brasil
VINúcleo de Medicina Tropical, Universidade de Brasília, Brasília, DF, Brasil
This study sought to verify the correlation between leprosy types and the adverse effects of treatment drugs. This quantitative, prospective, nested study was developed at the Dona Libânia Dermatology Centre in Fortaleza, Brazil. Data were collected from November 2007-November 2008. During this period, 818 leprosy patients were diagnosed and began treatment. Forty patients with tuberculoid leprosy (TT) were selected. Twenty patients followed a standard therapy of dapsone and rifampicin and 20 were administered dapsone, rifampicin and clofazimine (U-MDT). Twenty patients with borderline lepromatous (BL) and lepromatous leprosy (LL) were also selected and treated with U-MDT. All of the subjects received six doses. With the exception of haemolytic anaemia, there was a low incidence of adverse effects in all the groups. We did not observe any differences in the incidence of haemolytic anaemia or other side effects across groups of patients with TT, BL or LL treated with U-MDT.u00a0
A turning point in leprosy therapy occurred in 1981 when the World Health Organization (WHO) recommended using multidrug therapy (MDT), with dapsone and rifampicin for six months for paucibacillary (PB) patients (MDT-PB) and 24 months of dapsone, rifampicin and clofazimine for multibacillary (MB) patients (MDT-MB). In 1998, the WHO recommended a fixed duration of 12 months for treating MB patients (WHO 1998). The current WHO recommended treatment regimen for MB patients is 12 600 mg doses of rifampicin once a month, 300 mg of clofazimine once a month plus 50 mg daily and 100 mg of dapsone daily. For PB patients, the regimen is six 600 mg doses of rifampicin once a month and 100 mg of dapsone daily.
Despite the efficacy of the currently recommended leprosy MDT (Cellona et al. 2003, Morel 2004, Penna et al. 2011), there are some limitations, such as a prolonged treatment duration that leads to high drop-out rates, difficulties in general health practitioners classifying the clinical types and wrong diagnoses of the PB and MB types when based solely on the number of lesions (Huikeshoven 1985, Ellard et al. 1988, Dasamanjali et al. 1997). Such difficulties have led several researchers to search for a uniform and shorter MDT (U-MDT) for the different leprosy types (Ji & Saunderson 2003, Talhari & Penna 2005) to replace the current regular MDT (R-MDT) that requires six and 12 months of treatment for PB and MB patients, respectively. Recently, the WHO raised the possibility that PB and MB patients might be treated for six months (WHO 2002) based on the following factors: MDT has been proven efficacious and safe, there are very few reports of MDT resistance and relapse rates are low (< 1%) (Gelber et al. 2004, Matsuoka et al. 2007, WHO 2009).
Although U-MDT can represent an important advance in disease control, the recognised differences between the multi and PB groups should be considered, such as the bacillary charge (Ji 2001, Ji & Saunderson 2003), histopathological findings (Sarno & Sampaio 1996) and immunological (Goulart et al. 2002) and genetic (Mira et al. 2004, Moraes et al. 2004) profiles. Consequently, there is great concern regarding the possible impacts of U-MDT over several aspects of leprosy treatment, particularly therapy efficacy among MB patients and the incidence of adverse drug reactions in the patients with the PB type.
In 2007, an independent Brazilian study, the Brazilian U-MDT Clinical Trial (U-MDT/CT-Br), was initiated; in the study, dapsone, rifampicin and clofazimine were administered over six months to all leprosy patients (LPs). Here, we present the results of an investigation that was performed in the context of the U-MDT/CT-Br project with respect to comparing the incidence of adverse effects in two situations: (i) PB and MB patients who were treated with the same regimen (U-MDT) and (ii) PB patients who were treated with either the PB (R-MDT) or the MB (U-MDT) regimen. We hope our results will be useful in supporting the decision making process for implementing U-MDT as an efficacious disease control strategy (Penna 2011).
SUBJECTS, MATERIALS AND METHODS
This study is part of an independent study (U-MDT/CT-Br) coordinated by the Tropical Medicine Depart-ment of the University of Brasília (UnB) with the participation of the Institute of Public Health and Tropical Pathology of the Federal University of Goiás; funding was provided by the DECIT/CNPq (403293/2005-7). This study was conceptualised, designed and developed by the Tropical Medicine Department of the UnB in partnership with the Royal Tropical Institute of Amsterdam.
This quantitative, prospective, nested study was developed at the Dona Libânia Center for Dermatology (CDERM) in Fortaleza, state of Ceará, Brazil. The data were collected from November 2007-November 2008. The targeted patients were those with diagnosed leprosy who were treated at the CDERM in the U-MDT/CT-Br study. The U-MDT/CT-Br is an open label randomised clinical trial design that was used to compare two treatment regimens (R-MDT treatment vs. U-MDT treatment) with monthly follow-ups for up to one year post-treatment followed by yearly post-treatment visits for six years. Newly diagnosed, previously untreated PB and MB LPs, returning defaulters and relapse cases (provided that the last treatment dose was more than 5 years prior) ranging from six- 65 years of age were included in the study. Patients who were under tuberculosis treatment, steroid treatment, with overt signs of acquired immune deficiency syndrome or were unable to make monthly clinic visits during the treatment and follow-up periods were excluded. After being classified as either PB or MB based on the number of skin lesions, the patients were randomised and allocated into the trial. A random list of numbers for the study entrance sequence (according to the clinical report forms number) was prepared and the randomisation codes on the worksheet were covered with the same material that is used for lottery scratch cards; therefore, the printed numbers were not visible.
During the study period, 818 patients (all residents of the Fortaleza metropolitan area) were diagnosed with leprosy and began treatment at the centre. Out these patients, 430 were evaluated and 60 who presented with tuberculoid, borderline lepromatous (BL), or lepromatous leprosy (LL) types were selected based on unambiguous, rigorous, clinical, bacteriological and histopathological criteria according to the Ridley and Jopling (1966) classification. These 60 patients were distributed into three groups. Forty PB patients were divided into two sub-groups: (i) 20 patients were treated with MDT-PB treatment and (ii) 20 with the MDT-MB for six months. The 20 MB remaining patients (14 LL and 6 BL leprosy) were treated with MDT-MB for six months. None of the patients were removed from the study. The following exclusion criteria were applied: (i) patient wished to discontinue participation due to unavailability, procedure intolerance or any other personal reason, (ii) non-compliance with the experimental protocol, (iii) violation of the protocol, such as a histological finding that does not confirm leprosy, (iv) severe adverse events and/or signs or symptoms of possible severe toxicity, (v) patient's death during the study period, (vi) any other condition judged by the investigator to be necessary to maintain the health of the volunteer.
The data were prospectively collected during the seven visits, as shown in Table I. The objective of the first visit was to select patients who had never received treatment. On the second visit (day 8 of the study), the clinical classification was performed and the patients received the first supervised treatment dose. On the third visit (study day 9), recent adverse effects were evaluated and the study discontinuation criteria were addressed. On the fourth visit (day 15 of the study), late adverse effects were evaluated and the study discontinuation criteria were addressed. On the fifth visit (day 36), the adverse effects and possible study discontinuation were evaluated and the second supervised treatment dose was administered. The same procedures were performed on the sixth visit (day 148) and the final supervised dose of the treatment was administered. Finally, on the seventh visit (day 176 of the study), adverse effects were again evaluated and the patients were released.
The following adverse effects were monitored in the three groups: decreases in red blood cells (RBCs), haematocrit, haemoglobin, leucocytes and platelets, increases in the medium corpuscular volume, reticulocytes, C reactive protein (CRP), bilirubin, leukocytes and serum activities of lactate dehydrogenase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and alkaline phosphatase and the presence of jaundice, haepatomegaly, epigastric pain, nausea, anorexia, vomiting, abdominal pain, diarrhoea, dizziness, fatigue, headache, methemoglobinaemia, cyanosis, dyspnoea, psychosis, peripheral neuropathy, sulphone syndrome, agranulocytosis, acne, renal failure, flu-like syndrome, cutaneous pigmentation, xeroderma, constipation, acute abdominal pain, weight loss, lower limb oedema and drug-induced skin disorders (Cook 1995, Matsuoka et al. 2007, Harminder et al. 2011).
Statistical analysis - The statistical analysis of the association between the variables (adverse effects of drugs used in the MDT for leprosy) and the study groups (PB MDT-PB, PB MDT-MB and MB MDT-MB) was performed using the non-parametric chi-squared test and the probability ratio. The adverse effects were grouped according to the most likely causative drug.
Ethic - The U-MDT/CT-Br study was performed under the International (Helsinki) and Brazilian research regulations involving humans and was approved by three regional ethical committees from all of the states involved and by the National Ethics Commission. Written informed consent was obtained from all the patients prior to inclusion in the study. For patients aged six-17 years, written parental consent was obtained. Data confidentiality was guaranteed and the patients were free to leave the study and opt for the R-MDT regimen at any time (ClinicalTrials.gov identifier - NCT00669643).
In addition, informed consent forms specifically prepared for this study were presented to the Ethical Committee on Research of the CDERM and approved by the National Ethics Commission of Research - National Health Council/Ministry of Health, on February 17 2006, protocol 001/06.
Tables II-IV describe the frequency of the adverse effects that were observed in each patient group according to the drug most likely to be the cause of the adverse effect. Haemolytic anaemia was the most frequent adverse effect, particularly in the groups treated with MDT-MB. Of the PB patients under MDT-MB, 30% presented with a haemoglobin index of < 10 g%, while none of the patients under MDT-PB presented with a haemoglobin index of < 10 g%. Accordingly, we observed a statistically significant difference (p <0.05) between the PB groups on MDT-PB and MDT-MB in the distribution of the haematological alterations of the RBC index. No other statistically significant difference was observed between the groups.
To advance the understanding of the impact of MDT on the RBC index and the severity of haemolytic anaemia, the three groups were compared with respect to their distribution of haemoglobin values (obtained in the 6th month of treatment), as shown in Tables IV, V. Again, statistically significant differences were observed only in the comparison between the PB groups undergoing the MDT-PB and MDT-MB treatments.
Of the adverse drug effects that were observed in the three study groups, haemolytic anaemia appeared with the greatest frequency, accompanied by the symptoms classically associated with it, such as headache, fatigue and dizziness. Such data suggest that administering folic acid would serve as a preventive and/or therapeutic measure for all patients undergoing MDT.
The highest incidence of haemolytic anaemia was in the PB (95%) and MB groups (100%) treated with MDT-MB. A comparison to the PB patients who were treated with MDT-PB (65%, p < 0.05) suggests a role for clofazimine in developing these adverse effects (Chan-Tompkins 1995).
Upon analysing the severity of anaemia at the end of the sixth month of treatment, no differences were observed between the MB and PB patients under MDT-MB (25% vs. 30%, respectively) (Table VI), which indicates that the type of leprosy does not impact the severity of haemolytic anaemia. Instead, the statistically significant difference (p < 0.05) among the PB patients undergoing MDT-MB or MDT-PB suggests a possible influence of clofazimine on the severity of haemolytic anaemia (Katoch et al. 1999).
Note that haemolytic anaemia, in addition to being infrequent, did not reach a degree of severity to indicate the suspension of dapsone and/or clofazimine for any of the patients. This observation, in conjunction with the possibility of controlling the condition with folic acid, argues in favour of the viability of MDT/MB for PB patients.
Finally, the adverse effects of dapsone, clofazimine and rifampicin were similar across the PB and the MB groups under MDT-MB, even after considering haemolytic anaemia (95% vs. 100%). Furthermore, none of the other adverse effects were identified at a frequency or severity that would indicate medical intervention. It is important to further highlight the absence of severe adverse effects attributed to dapsone (e.g., methemoglobinaemia, sulphone syndrome and agranulocytosis), rifampicin (renal failure or flu-like syndrome), or clofazimine (semi-occlusion, intestinal occlusion and acute abdominal pain) (Cook 1995). Despite this result, the total number of LPs worldwide using these drugs suggests strict surveillance of the adverse effects of MDT. In a literature search, we did not identify any studies that found synergistic effects of clofazimine and dapsone in the genesis of adverse effects in LPs. Additionally, there were no large controlled studies of the real prevalence of the adverse effects of R-MDT for comparison with our study.
Although PB and MB LPs presented bacteriological, immunological, histopathological, clinical and genetic differences, no differences in the incidence of adverse effects were observed in this study. Therefore, it is possible that the differences between PB and MB leprosy types have no influence on the pharmacokinetics of dapsone, rifampicin and clofazimine.
To Dr Marcelo Távora Mira (PUC-Paraná), Dr Maria Lúcia Fernandes Penna (UFF) and Dr Sinésio Talhari (UNL-AM), for their critical analysis and collaboration in the preparation of this paper.
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