Rifampicin chemoprophylaxis in preventing leprosy in contacts of patients with leprosy: a comprehensive systematic review protocol Lesional characteristics and histopathology in paucibacillary leprosy patients with 2 or 3 skin lesions: comparison between ROM and PB-MDT regimens. Efficacy of single-dose chemotherapy (rifampicin, ofloxacin and minocycline-ROM) in PB leprosy patients with 2 to 5 skin lesions, India: randomised double-blind trial. Room for improvement? A survey of the methods used in systematic reviews of adverse effects Photodynamic therapy for acne vulgaris: a randomized, controlled, split-face clinical trial of topical aminolevulinic acid and pulsed dye laser therapy. Can you believe what you read in the papers? Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): Results of an open label, randomized and controlled clinical trial, among multibacillary patients
Review question / objective What is the effectiveness of rifampicin chemoprophylaxis in preventing leprosy in contacts of patients with leprosy ? What are the experiences and acceptability with the use of rifampin chemoprophylaxis in the prevention of disease from contacts with patients who have leprosy , in patients with leprosy following treatment and in family and health care professionals ? Background Leprosy is globally acknowledged as a millenary and stigmatizing disease and a condition with attributed consequences such as physical deformities and disabilities . From a multi‐causal perspective , there is evidence that leprosy occurs more often in men than in women , is distributed across all age groups and occurs mainly among people living in unfavorable socioeconomic circumstances , who are also the most affected by public segregation policies . 1–4 In 2013 , a total of 215,656 new cases of leprosy were detected worldwide . Regions with the highest number of cases are Southeast Asia ( 72.1 % ) the Americas ( 15.3 % ) . Whereas the countries with the highest prevalence were India ( 58.8 % ) and Brazil ( 14.4 % ) . 5 Hansen 's bacillus ( Mycobacterium leprae ) is considered a microorganism of high infectivity and low pathogenicity and virulence . It is transmitted via nasal oropharyngeal secretions and breaks in the skin of infected patients . Therefore , the main form of transmissibility is inter‐human and the greatest risk of contagion is cohabitation with these patients .1–3 It is estimated that most individuals have a natural resistance to Mycobacterium leprae ( M. leprae ) and that some are prone to developing a severe form of the disease , the multibacillary forms . Studies on exogenous reinfection and endogenous reactivation in chronic diseases , such as tuberculosis and leprosy , show that susceptible individuals become infected by the bacillus through contact with multibacillary patients .1–3,6,7 The surveillance of leprosy contacts is a priority action for control of the disease . Children are exposed to the highest risk of becoming infected by being in contact with a family member or anyone close to them who has the disease . Having a current case of leprosy in the family is associated with a 2.9 times greater risk of a healthy family member becoming infected , and that risk increases when the family has a history of the disease.3,6–9 Bakker et al.7 reported that household contacts of multibacillary patients presented a four times greater risk of becoming infected with the disease compared to non‐contacts . For Ximenes et al.,10 the condition of being a contact of individuals with leprosy represented twice the risk of retreatment due to recurrence in relation to the control group . Therefore , alternative or complementary strategies , such as chemoprophylaxis , must be sought as a form of prevention of the disease . Chemoprophylaxis is defined as the administration of drugs capable of preventing an infection or keeping infected individuals from falling ill . In leprosy , the preventive strategy consists of employing medications to prevent the infection by M. leprae in people with a higher risk of exposure to the disease , i.e. those in contact with the patient . Therefore , chemoprophylaxis plays an important role in the protection of individuals vulnerable to the disease . However , studies regarding its effective utilization are inconclusive.11–15 The first investigations of the utilization of prophylaxis in leprosy contacts in the 1960s and 1970s included dapsone and acedapsone and later in the 1980s and 1990s rifampicin . However , interest in this type of research decreased after 1982 when the World Health Organization ( WHO ) introduced multidrugtherapy ( MDT ) for the treatment of leprosy.16–19 Multidrugtherapy is a combination of three drugs , dapsone , rifampicin and clofazimine , to prevent the selection of resistant strains . As of 1997 , the WHO adopted the alternative rifampicin , ofloxacin and minocycline ( ROM ) regimen , recommended for paucibacillary cases with a single lesion without the involvement of nerve stems.19,20 Adoption of these measures was expected to result in a reduction in the incidence of leprosy as a public health problem ; however , the observed result was not significant in terms of reducing the incidence of newly detected cases . Furthermore , considering the evidence of resistance to monotherapy with dapsone , there was a rise in interest in intervention studies , particularly using rifampicin in household and community contacts.1,2,5,11,12 However , some studies have indicated little or no protection against the disease through the use of rifampicin . While Moet et al.14 and Feenstra et al.21 observed protection of two years in household contacts with a single dose of rifampicin , Bakker et al.13 showed no difference between the experimental group and the control group with two doses of rifampicin , 600 mg for adults and 300 mg for children . Another study of people at high risk of contracting the disease that used a single dose of ROM and rifampicin showed that there was a reduction of type immunoglobulin M antibodies among adults in both interventions .22 Meta‐analyis of dapsone , acepdapsone and rifampicin compared with placebo showed that chemoprophlasys is an effective measure to prevent leprosy . 12 Currently , strategies using a combination of the Bacillus Calmette‐Guérin ( BCG ) and chemoprophylaxis with rifampicin in leprosy contacts appear to be complementary measures for protection against the disease . This strategy showed a protective effect of 80%.23 Studies of acceptability and experience of chemoprophylaxis to control leprosy with individuals and health professionals are scarce . In a qualitative study , Feenstra et al.24 concluded that chemoprophylaxis for household contacts of leprosy patients is an effective and socially acceptable addition to the current leprosy control program . A preliminary search of the Joanna Briggs Data base of Systematic Review s and Implementation Reports , the Cochrane Library , CINAHL , PubMed and PROSPERO has revealed that there are no systematic review s ( either published or underway ) on this topic . In this context , it is un question ably useful to integrate the scientific evidence from studies that evaluated the effectiveness of the rifampicin chemoprophylaxis in leprosy contacts , the experiences and acceptability of contacts of leprosy patients , patients with leprosy following treatment and family and health care professionals about this strategy for the prevention of the disease . This knowledge can support the measures adopted to reduce endemicity , which strengthens the quality of the care delivered to the population most vulnerable to becoming ill . Operational definitions : Leprosy patients : individuals who present one or more of the following cardinal signs and who require multidrugtherapy : lesion(s ) and /or skin areas with altered sensitivity ; affected peripheral nerve(s ) , with or without thickening , associated with sensitive and /or motor and /or autonomic changes ; and a positive skin smear bacilloscopy . Cases are classified as paucibacillary or multibacillary based on the number of lesions and /or bacilloscopy when available ; cases are considered paucibacillary when patients present five or fewer skin lesions and /or negative bacilloscopy , corresponding to the undetermined and tuberculoid clinical forms ; multibacillary cases are when patients present more than five skin lesions and positive bacilloscopy , corresponding to the dimorphous and Virchow 's forms of the disease.1–4,25 Leprosy case : term used in epidemiology to identify individuals with leprosy for purpose s of monitoring the health conditions of a population .2,26 Chemoprophylaxis : the administration of drugs capable of preventing the infection or keeping infected individuals from falling ill.11,12 Contacts : those who cohabit or have cohabited with leprosy patients .12,14,21 Index case : the first case of the disease among several similar cases that are epidemiologically related with the secondary case ( index case contacts).21 Recurrence : the reappearance of signs and symptoms of the disease after recuperation from a first occurrence of the disease , usually within five years.6,10,27 Treatment ab and onment : interrupting treatment for over twelve months.6,10 Therapeutic regimen established for confirmed leprosy cases : for paucibacillary ( PB ) cases , six monthly supervised doses of rifampicin ( RFM ) 450‐600 mg , and daily self‐administered doses of dapsone ( DDS ) 50‐100 mg , for up to nine months ; for multibacillary ( MB ) cases , twelve supervised monthly doses of rifampicin ( RFM ) 450‐600 mg and clofazimine ( CFZ ) 100‐300 mg , associated to daily self‐administered doses of dapsone ( DDS ) 50‐100 mg and CFZ 50 mg , for up to 18 months . An alternative treatment for MB is 24 doses within 36 months.1,2,19 Rifampicin chemoprophylaxis regimens : single‐dose rifampicin of 25 mg/kg or monthly dose for six months ; double‐dose rifampicin or combined regimens of ROM ‐ rifampicin ( 600 mg ) , ofloxacin ( 400 mg ) and minocycline ( 100 mg ) , according to body weight.13–15,21 Efficacy/effectiveness : proof ( or not ) of successful intervention . Efficacy is the result of an intervention performed under ideal , well‐controlled conditions , such as in r and omized clinical trials . Effectiveness refers to the result of an intervention applied under usual medical practice conditions.28 Operational classification : paucibacillary and multibacillary.1,2 , 25 Comorbidities : morbidities possibly associated with leprosy , such as tuberculosis , diabetes , HIV/AIDS , and others.1,2  BCG vaccination scar : result ing from the intradermal injection of Bacillus Calmette‐Guérin ( BCG ) vaccine on the deltoid , used to prevent tuberculosis and leprosy.23,29 Adverse events : negative effects result ing from the actions of drugs.1,2 Incidence rate : measures the frequency or likelihood of new cases of diseases occurring in a population .30 Estimated effect of an intervention : shows the theoretical distribution of possible effects Paucibacillary ( PB ) patients form a large segment of newly diagnosed leprosy patients and those who present with only two or three skin lesions could have problems with compliance . With prolonged anti-leprosy drug regimens that last over six months . ROM therapy , a one-dose regimen , offers an attractive alternative in treating such patients . We conducted a longitudinal study of 51 such PB patients , placing them in two groups at r and om : one receiving the st and ard PB-MDT regimen , and the other the ROM regimen . Patients were followed up for 2 years , with a comprehensive clinical examination done every six months . 14 patients , 7 in each group , also had their skin biopsies evaluated histopathologically at recruitment , at 6 months and at the end of 2 years . There was a consistent improvement of lesions in both the groups over time . The fall in granuloma fraction and the clearance of the initial bacterial index were seen in the histopathology of both groups . Although the PB-MDT regimen is an effective and robust one , the operational convenience and drug compliance with ROM could make it an acceptable , parallel regimen for PB patients when the disease is localized to 2 or 3 skin lesions UNLABELLED We conducted r and omized double-blind trial for single-dose of Rifampicin , Ofloxacin and Minocycline ( ROM ) compared to WHO-PB-MDT among paucibacillary ( PB ) leprosy patients with 2 - 5 skin lesions . We enrolled 1526 patients from five centres ( ROM=762 ; WHO-PB-MDT=764 ) and followed them for 36 months posttreatment during 1998 - 2003 . We generated information on clearance of skin lesions and relapse rates per 100 person-years ( PY ) for all the five centres . At base-line , the patients in the two arms were comparable . Complete clearance of skin lesions was similar ( 72 % vs. 72.1 % ; p=0.95 ) in both the arms . Clinical scores declined steadily and equally . Difference in relapse rates was statistically highly significant ( ROM=1.13 and WHO-PB-MDT=0.35 per 100 PY ; mid-p exact=0.001016 ) . Twenty eight of 38 of these relapses occurred within 18 months . In all , 10 suspected adverse drug reactions were.observed ( ROM=2 ; WHO-PB-MDT=8 ) . We extended the follow-up to 48 months for 1082 of 1526 patients from two programme-based centres . No further relapses occurred . Decline in clinical score was not dependent on age , gender , number of lesions or affected body parts . Single dose ROM , though less effective than the st and ard WHO-PB-MDT regimen conceptually offers an alternative treatment regimen for PB leprosy patients with 2 - 5 lesions only when careful follow-up for relapse is possible . Registered at the Clinical Trials Registry of India ; REGISTRATION NUMBER Background Although the methods for conducting systematic review s of efficacy are well established , there is much less guidance on how systematic review s of adverse effects should be performed . Methods In order to determine where method ological research is most needed to improve systematic review s of adverse effects of health care interventions , we conducted a descriptive analysis of systematic review s published between 1994 and 2005 . We search ed the Data base of Abstract s of Review s of Effects ( DARE ) and The Cochrane Data base of Systematic Review s ( CDSR ) to identify systematic review s in which the primary outcome was an adverse effect or effects . We then extracted data on many of the elements of the systematic review process including : types of interventions studied , adverse effects of interest , re sources search ed , search strategies , data sources included in review s , quality assessment of primary data , nature of the data analysis , and source of funding . Results 256 review s were included in our analysis , of which the majority evaluated drug interventions and pre-specified the adverse effect or effects of interest . A median of 3 re sources were search ed for each review and very few review s ( 13/256 ) provided sufficient information to reproduce their search strategies . Although more than three quarters ( 185/243 ) of the review s sought to include data from sources other than r and omised controlled trials , fewer than half ( 106/256 ) assessed the quality of the studies that were included . Data were pooled quantitatively in most of the review s ( 165/256 ) but heterogeneity was not always considered . Less than half ( 123/256 ) of the review s reported on the source of funding . Conclusion There is an obvious need to improve the methodology and reporting of systematic review s of adverse effects . The methodology around identification and quality assessment of primary data is the main concern BACKGROUND There remains the need for more effective therapeutic options to treat acne vulgaris . Interest in light-based acne treatments has increased , but few r and omized , controlled clinical trials assessing the value of photodynamic therapy ( PDT ) for acne have been reported . AIMS We sought to examine the efficacy of PDT using 5-aminolevulinic acid ( ALA ) and pulsed dye laser therapy in the treatment of acne . PATIENTS / METHODS We conducted a r and omized , controlled , split-face , single-blind clinical trial of 44 patients with facial acne . Patients were r and omized to receive three pulsed dye laser treatments to one side of the face after a 60 - 90 min ALA application time , while the contralateral side remained untreated and served as a control . Serial blinded lesion counts and global acne severity ratings were performed . RESULTS Global acne severity ratings improved bilaterally with the improvement noted to be statistically significantly greater in treated skin than in untreated skin . Erythematous macules ( remnants of previously active inflammatory lesions ) decreased in number in treated skin when compared with control skin and there was a transient but significant decrease in inflammatory papules in treated skin when compared with untreated skin . There were no other statistically significant differences between treated and untreated sides of the face in terms of counts of any subtype of acne lesion . Thirty percent of patients were deemed responders to this treatment with respect to improvement in their inflammatory lesion counts , while only 7 % of patients responded in terms of noninflammatory lesion counts . CONCLUSIONS PDT with the treatment regimen employed here may be beneficial for a subgroup of patients with inflammatory acne The number of reports of clinical trials grows by hundreds every week . However , this does not mean that people making decisions about healthcare are finding it easier to obtain reliable knowledge for these decisions . Some of the information is unreliable . Systematic review s are helping to resolve this by bringing together the research on a topic , appraising and summarising it . But the quality of these review s depends greatly on the quality of the studies , and this usually means the quality of their reports . If there are fundamental flaws within a study , such as the use of inappropriate ' r and omisation ' techniques in the context of review s of the effects of interventions , the review ers will not be able to fix these . Worse still , if they are not aware of underlying flaws , they might make incorrect judgements about the quality of the research in their review . A study by Wu and colleagues of ' r and omised trials ' from China provides a reminder of the cautious approach needed by users of scientific articles . They contacted the authors of more than 2000 research articles , which purported to be reports of r and omised trials ; and concluded that ten of every 11 studies cl aim ing to be a r and omised trial probably did not use r and om allocation . Better education of research ers , peer review ers and editors about what is , and is not , a properly r and omised trial is needed ; along with better reporting of the details for how participants were allocated to the different interventions . Systematic review ers must be cautious in making assumptions about the conduct of trials based on simple phrases about the trial methodology , rather than a full description of the methods actually used . It 's not that you ca n't believe anything that you read in the papers , just that you can not believe everything Background Leprosy control is based on early diagnosis and multidrug therapy . For treatment purpose s , leprosy patients can be classified as paucibacillary ( PB ) or multibacillary ( MB ) , according to the number of skin lesions . Studies regarding a uniform treatment regimen ( U-MDT ) for all leprosy patients have been encouraged by the WHO , rendering disease classification unnecessary . Methodology and findings An independent , r and omized , controlled clinical trial conducted from 2007 to 2015 in Brazil , compared main outcomes ( frequency of reactions , bacilloscopic index trend , disability progression and relapse rates ) among MB patients treated with a uniform regimen/U-MDT ( dapsone+rifampicin+clofazimine for six months )  versus WHO regular-MDT/R-MDT ( dapsone+rifampicin+clofazimine for 12 months ) . A total of 613 newly diagnosed , untreated MB patients with high bacterial load were included . There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups , with more than 25 % disability progression in both groups . The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group . During active follow up , four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up ( 95 % CI [ 0·81 , 6·2 ] per 1000 ) . During passive follow up three patients relapsed in U-MDT and one in R-MTD . As this period corresponds to passive follow up , sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year . Conclusion Our results on the first r and omized and controlled study on U-MDT together with the results from three previous studies performed in China , India and Bangladesh , support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide . Trial registration Clinical Trials.gov :
The most under-reported items were concealment of allocation , blinding of patients and outcome assessors , intention to treat and validation of outcomes .
BACKGROUND In the process of conducting a systematic review on interventions for skin lesions due to neuritis in leprosy , we assessed several primary papers with respect to the quality of reporting and methods used in the studies .
Awareness of what constitutes weak points in previously conducted studies may be used to improve the planning , conducting and reporting of future clinical trials .
AIMS To assess the quality of reporting and of methodology  in studies of interventions for skin lesions due to neuritis in leprosy .