Interventions for Old World cutaneous leishmaniasis Edited (no change to conclusions)

Abstract

Abstract Background

Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low‐ and middle‐income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008.

Objectives

To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis.

Search methods

We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co‐ordinators, directors, clinicians, WHO‐EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE.

Selection criteria

Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound.

Data collection and analysis

Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search.

Main results

We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.

Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.

In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow‐up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.

When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow‐up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.

Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons.

Authors' conclusions

There was very low‐certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.

We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well‐designed international studies that evaluate long‐term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.

It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.

Author(s)

Julio Heras‐Mosteiro, Begoña Monge‐Maillo, Mariona Pinart, Patricia Lopez Pereira, Ludovic Reveiz, Emely Garcia‐Carrasco, Pedro Campuzano Cuadrado, Ana Royuela, Irene Mendez Roman, Rogelio López‐Vélez

Abstract

Plain language summary

Treatments for Old World cutaneous leishmaniasis

Background

Old World cutaneus leishmaniasis (OWCL) is an infection caused by the Leishmania parasite, which is passed onto humans by the bite of sandflies. It is a serious skin disease associated with a broad range of signs, symptoms, and degrees of severity. We wanted to assess the competence and safety of all available treatments for OWCL.

Review question

We assessed participants with a healthy immune response who had OWCL diagnosed by laboratory methods. Treatments had to be given alone or in combination with another treatment, and they were compared against no treatment, placebo (an inactive substance) only, or another active treatment. Some of the main outcomes we were interested in included the percentage of wounds cured after the end of treatment, the number of participants completely cured after the end of treatment, speed of healing, side‐effects of treatment, and clearance of parasites (i.e. infection).

Study characteristics

We reviewed 89 clinical trials, which included 10,583 people, in total, with OWCL. We included participants of both sexes and all ages (mean 24.5 years); most participants were over 18 years of age. Most studies were carried out in single centres in different countries, mainly in the Far or Middle East, and lasted between two to six months. We included a variety of treatments, such as antimonials, antifungals, and antibiotics, which were administered either directly onto the skin or into a wound, taken by mouth, or physically applied (e.g. laser treatment, heat therapy, etc.). Most of the included studies assessed OWCL caused by two species of parasites known as Leishmania major (L. major) andLeishmania tropica (L. tropica).

Key results

The evidence is current to November 2016.

Two of the most important treatments that we assessed in this review were itraconazole, an antifungal drug taken by mouth, and paromomycin, an antibiotic applied as an ointment. Trials compared both to a placebo tablet or inactive cream (vehicle).

Participants received 200 mg itraconazole for six to eight weeks or paromomycin ointment at a concentration of 15% plus 10% urea, twice daily for 14 days.

When assessed on average 2.5 months after treatment, more participants were completely cured and cleared of the infection‐causing parasites with itraconazole than placebo, but they also had more side effects (mild stomach pain, sickness, and abnormal liver function, as well as headaches and dizziness).

When paromomycin ointment was compared with placebo, there was no difference in the number of completely cured participants or the number who were found to be cleared of parasites when assessed on average 2.5 months after treatment, but those in the paromomycin treatment group had more contained skin reactions (such as swelling, blistering, pain, redness, or itch).

However, as the certainty of the evidence for these outcomes for these particular comparisons was very low, we are not sure of the accuracy of these results.

Neither of our key treatment comparisons assessed the percentage of wounds cured after the end of treatment and speed of healing (i.e. time taken to be cured).

Quality of the evidence

The overall certainty of the evidence for the different outcomes in the two main comparisons was very low. Important reasons for this were that studies were not blinded, or had a small sample size, making the results less precise. Some of the evidence only focused on young people, and the results greatly varied between each study.

We need more research to fill in the following research gaps: 1) trials of OWCL caused by other types of infection such as L. infantum, L. aethiopica,or L. donovani; 2) involving specific subgroups of people such as children; 3) assessing effectiveness and safety of different anti‐Leishmania drugs compared with placebo in self‐healing forms of leishmaniasis or with traditional first‐choice antimonial treatment in complicated form (defined as more than four lesions over 4 cm in size, located close to an opening or small joints, for which previous treatment has failed); and 4) assessing areas such as wound healing and patient‐reported outcomes, such as quality of life. In addition, few studies assessed relevant issues such as drug resistance. International collaboration is required to improve the quality and standardisation of future trials in order to develop a better evidence‐based approach.

Author(s)

Julio Heras‐Mosteiro, Begoña Monge‐Maillo, Mariona Pinart, Patricia Lopez Pereira, Ludovic Reveiz, Emely Garcia‐Carrasco, Pedro Campuzano Cuadrado, Ana Royuela, Irene Mendez Roman, Rogelio López‐Vélez

Reviewer's Conclusions

Authors' conclusions

Implications for practice

We have updated information from randomised controlled trials (RCTs) of treatments for Old World cutaneous leishmaniasis (OWCL) and summarised the best available evidence using quantitative and qualitative methods. We have endeavoured to provide information to help clinicians choose the most appropriate treatment. We have been careful not to be too prescriptive because the purpose of this systematic review is to present information rather than offer advice.

There are few treatments for CL with robust evidence from multiple randomised trials. This may be because OWCL can heal spontaneously – in many cases within a couple of months – without any need for therapeutic intervention. L major‐caused CL can heal spontaneously in 40% to 70% of cases at 3 months and close to 100% at 12 months. Spontaneous cure rates for L tropica‐caused CL are 1% at 3 months, 68% at 12 months, and usually close to 100% in three years (Asilian 1995; Ben Salah 1995; Zakraoui 1995). Therefore, in many cases people with CL do not receive any drug. When clinicians do prescribe treatment, they usually prefer less toxic local treatments, reserving systemic treatments (azole drugs, miltefosine, antimonials, amphotericin B formulations) for complex cases.

We cannot make firm recommendations about the use of our two key comparisons.

  • Itraconazole versus placebo.
  • Paromomycin ointment (15% plus 10% urea) versus vehicle.

Due to the very low certainty of the evidence, and even though our analyses favoured itraconazole in terms of complete cure and lesions cured, we cannot be sure our results are conclusive. Similarly, although we found no difference between paromomycin ointment and vehicle in terms of these same outcomes, the very low certainty of the evidence casts doubt on our results, as it also does we do when we report more mild adverse effects with itraconazole and paromomycin ointment.

Our other key outcomes of microbiological or histopathological cure of skin lesions and speed of healing (i.e. time taken to be cured) were not measured for these key comparisons. None of the included studies assessed participant‐focused measures of success, such as quality of life and degree of functional and aesthetic impairment.

We have identified gaps in knowledge that imply difficulties and limits in terms of clinical practice. RCTs that compare local versus systemic treatment are scarce, and the results discordant.

Also, there is in many cases a lack of knowledge on when treatment is really needed, since OWCL can also heal spontaneously.

Although we included 89 studies in this review, most of them explore different therapeutic regimens: not only different drugs, but even the same drug administered locally or systemically or with different doses or regimens. This means that only one RCT evaluated most regimens with a specific Leishmania species and with a different clinical presentation, which may reduce the strength of the recommendation and limit the possibility to extrapolate the results to other Leishmania species.

Twenty‐nine studies did not isolate the Leishmania species. This can make it difficult to apply the result to clinical practice because a particular therapeutic regimen may have good results among a specific Leishmania species but not with another OWCL species. In addition, the same Leishmania species may vary its response to a certain treatment when the only difference is the geographical area where the infection was acquired (Monge‐Maillo 2013). Therefore, it may be difficult for physicians to extrapolate the published results to their daily clinical practice.

Before starting treatment for localised CL, and especially in the zoonotic form, people with OWCL need to be informed of the possibility of spontaneous healing and the lack of evidence for some treatments. Healthcare practitioners can still play an important role in providing information and wound healing management even if there is no good evidence for any special regimen of healing support.

The eight studies in Studies awaiting classification may alter the conclusions of the review once assessed.

Implications for research

This updated systematic review has identified the need for large, well‐conducted RCTs to assess the benefits and harms of interventions for OWCL.

Design

We considered only one RCT to be at low risk of bias in all domains (Ranawaka 2015). To encourage the implementation of well‐designed clinical trials specifically aimed at developing effective treatments (both primary and adjuvant), González 2010 developed guidelines for clinical trials of cutaneous leishmaniasis. However, it is evident from the newly included RCTs that improvement of study quality and standardisation of outcomes is still needed. The COMET (Core Outcome Measures in Effectiveness Trials) Initiative (www.cometinitiative.org) is working to improve the standardisation of study outcomes by raising awareness of the need for systematised methodologies that acknowledge the complexity of CL and define reproducible, measurable, and clinically meaningful outcomes (Olliaro 2013). Future trials need to ensure they follow this guidance and also adhere to the CONSORT Statement (Schulz 2010), especially to improve the reporting of important bias domains, the causative parasite, and timing of outcome assessment. Future studies should also be sufficiently powered.

Resources are particularly limited for research into neglected diseases in LMICs, even those that present major public health problems. Cost and licensing entanglements (freedom to operate) need to be considered before investing money in conducting new trials. Prioritisation for clinical research in OWCL is a necessity.

Participants

A number of interventions are currently used in women of childbearing age and children, in those with comorbidities, and in immunocompromised individuals with no drug interactions. Future trials should assess safety and efficacy in those subgroups.

Leishmania species

The current evidence for different types of clinical management of OWCL and particularly for species such as L infantum,L aethiopica,L major,L tropica, andL donovani is either lacking or of very low quality. Eighteen studies did not even report the species of leishmaniasis, which can theoretically be easily determined with the use of new DNA techniques. However, these techniques require an investment in infrastructures that is unaffordable for the resource‐restricted laboratories located in disease‐endemic countries. Of the 23 studies that reported the Leishmania species, only 11 (48%) confirmed which caused the development of the disease, and the other 12 mentioned the endemic nature of a specific parasite strain and assumed it was the disease‐causing species. Since treatment sensitivity is species‐dependent, species identification is critical in future trials, for the choice of the best treatment outcome, with the fewest side effects and late complications (de Vries 2015).

Outcomes

None of the studies addressed measurements of quality of life, degree of functional and aesthetic impairment, or relevant issues such as drug resistance or change in ability to detect Leishmania. Outcomes evaluating participants' values and preferences are needed to ensure greater responsiveness of practice guidelines and support shared decision‐making.

With only limited data on prevention of scarring, the development of successful approaches to enhance wound healing or diminish scar formation within targeted areas, or both, will lead to a lower risk of developing scars in these sites. These issues are also possible future trial priorities.

Reducing adverse effects derived from treatment should also be a priority in research. Intramuscular or intravenous drugs are associated with more severe adverse effects. There is a need for less painful and better‐tolerated novel treatment modalities, particularly for children. Alternatives to intramuscular or intravenous treatments should be a research priority, as well as efficacious, well‐tolerated and inexpensive oral agents with enough sensitivity to treat all target species, with few serious adverse effects.

Future studies should assess the long‐term effects of treatment, as healing cannot be clearly confirmed without a long‐term assessment (e.g. at least six months after treatment has finished). For this, it is important to make an a priori decision about the postintervention time frame, based on the maximum length of time after the event during which improvement is attributed to the intervention (Goodman 2007).

Interventions

Future trials should aim at assessing the efficacy of treatments, ideally administered with a single dose of drug or with a short regimen, as this improves adherence. Other lines of research on interventions are for oral or self‐administered treatments requiring minimal supervision (the route of administration can be topical but oral is preferred).

Although frequently used and recommended for the treatment of localised OWCL, we found limited evidence on the use of wound healing to treat OWCL, so this is an important area to test.

Furthermore, as highlighted in the previous review, there is a need for more evidence of the effectiveness and safety of different anti‐Leishmania drugs compared with placebo in self‐healing forms of leishmaniasis or with traditional first‐line antimonials in complicated form, as the basis to recommend alternative safe, efficacious, and affordable treatments. The number of new studies using an active drug as a comparator has doubled, contrasting with fewer placebo‐controlled studies.

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