Topical treatments for HIV‐related oral ulcers

Abstract

Background

In HIV‐infected adults, oral ulcers occur more frequently, last longer and produce more painful symptoms than in immunocompetent people. Oral aphthous ulcers observed during the course of HIV infection may be severe and can result in significant morbidity in these patients. Such manifestations may interfere with oral functions and alter patients' quality of life.

Objectives

To evaluate the efficacy and side effects of topical agents used in the treatment of HIV‐related oral aphthous ulcers in adults.

Search methods

The following electronic databases were searched from the year 1980 to May 2011 for randomised controlled trials involving managements of oral ulcers, apthouses in HIV infected adults: EMBASE, PUBMED, the Cochrane Central Register of Controlled Trials (CENTRAL).

Selection criteria

Only randomised controlled trials that evaluated the efficacy of any topical agent in treating HIV oral aphthous ulcerations in HIV positive adults were considered.

Data collection and analysis

Two authors independently assessed the potentially eligible studies for inclusion. We did not find any studies that meet our eligibility criteria. Therefore, no analysis was performed.

Main results

A total of 233 abstracts were retrieved from the databases searched. None of the identified studies met our inclusion criteria. Ten of the studies identified were reports of systemic rather than topical treatment. Therefore, no studies were included in this review.

Authors' conclusions

There is a need for well designed studies to evaluate the efficacy and safety of topical agents for the treatment of HIV related oral aphthous ulcers.

Plain language summary

Topical treatments for HIV‐related oral ulcers

Oral aphthous ulcers associated with HIV infection occur commonly and recur frequently with varying severity. They occur at different stages of the disease. Topical treatments aim at meeting the basic requirements of the management of these ulcers which include pain relief, healing and reduction in recurrence. Topical treatment reduces the incidence of toxicity and serious side effects associated with systemic treatments. This review was conducted to evaluate the efficacy of the various topical agents available for the treatment of HIV related oral aphthous ulcers. From all the abstracts and articles examined, only two studies appeared to meet the inclusion criteria but had no full text reports, which makes it impossible to make recommendations.

Background

HIV/AIDS is currently the leading cause of death in adults in Africa and the sixth leading cause of death worldwide (Mathers 2009) . The HIV/AIDS epidemic is one of the most serious diseases to affect humanity (WHO 2008). Presently, about 4 million people become newly infected every year (UNAIDS 2006). In HIV infected adults, oral ulcers occur more frequently, last longer, and produce more painful symptoms than in immunocompetent people (Kerr 2003). A number of studies have demonstrated that about 40%‐50% of HIV‐positive people have oral fungal, bacterial, or viral infections, often occurring early in the course of the disease (WHO 2008). Oral ulcers observed during the course of HIV infection may be very severe and can result in significant morbidity in these patients. Such manifestations may interfere with oral functions and alter patients' quality of life.

The specific cause of these aphthous ulcerations in HIV patients remains unclear, but investigators have proposed a number of possible contributing factors, including overstimulation of tumour necrosis factor (Natah 2000), immune cross‐reactivity to infectious agents, nutritional deficiencies, stress, and hormonal imbalance (Scully 2003).

HIV related aphthous ulcers tend to be more severe in terms of their number, frequency, pain, and duration than non‐HIV related ones. Serum B12 and folate deficiency are predisposing factors for aphthae and although such deficiencies are not uncommon in HIV disease, HIV associated oral ulceration has been proposed to be independent of these factors (MacPhail 1997). Severe major aphthae may suggest very low CD4 counts and thus may signal disease progression(Ramos‐Gomez 1997).

Aphthous ulcers are generally classified as major, minor or herpetiform. Major ulcers can exceed 3cm in diameter and may develop into very large necrotic lesions. Major ulcers are seen more commonly in HIV‐infected than non‐infected adults, especially in individuals who have a CD4 count of less than 100cells/mm3 (MacPhail 1991). Minor ulcers measure less than 1cm in diameter, are shallow, and typically heal spontaneously within 1‐2 weeks without scarring in non‐infected patients and herpetiform is characterized by small, numerous 1‐3mm lesions that form clusters.

The oral lesions associated with HIV disease were classified by the European Community (EC) Clearinghouse on Oral Problems Related to HIV Infection (EC‐Clearinghouse 1993) and also by the US Workshop on Oral Manifestations in HIV Infection (Greenspan 1992) into:

• Oral lesions strongly associated with HIV infection: Oral candidiasis, pseudo‐membranous and erythematous; oral hairy leukoplakia; HIV gingivitis, linear gingival erythema, acute necrotizing ulcerative gingivitis and HIV periodontitis, acute necrotizing ulcerative periodontitis; Kaposi sarcoma (KS); non‐Hodgkin lymphoma (NHL) and others.

• Oral lesions less commonly associated with HIV infection: Acute necrotizing stomatitis, Mycobacterium tuberculosis, Ulceration not otherwise specified (NOS), herpes simplex virus, herpes zoster virus, and others.

• Oral lesions seen in HIV infection: Recurrent aphthous ulcer (RAS), cytomegalovirus ulcer, Histoplasma capsulatum, cat scratch disease, Molluscum contagiosum, and others.

This classification was revised by the Oral HIV/AIDS Research Alliance (OHARA), with some modifications and additions where these oral lesions were organized by their etiology into fungal, viral, and bacterial infections, idiopathic conditions, salivary gland disease and neoplasms (Shiboski 2009). Recurrent aphthous stomatitis, necrotizing ulcerative stomatitis and ulceration not otherwise specified (NOS), falls under the idiopathic category. An algorithm for HIV‐related oral lesion case definitions that summarizes clinical descriptors, symptoms and duration were also provided to improve diagnostic accuracy (Shiboski 2009).

Biopsy should always be performed on long‐standing ulcers because either infection or a neoplastic process may be present. In the absence of infection or neoplasm, such lesions then are designated as ulcerations not otherwise specified (NOS) ulcers (Ficarra 1997). Neoplastic ulceration is uncommon but may reflect NHL or squamous cell carcinoma (Flaitz 1995). Atypical Kaposi sarcoma may also present with ulceration. It is still uncertain whether oral squamous cell carcinoma is more prevalent in HIV disease; however, it does appear to affect a younger population in the absence of the usual risk factors (Ficarra 1994).

Management of oral aphthous ulcers depends on the severity of the lesions. The goals of current treatments are to promote ulcer healing, to reduce ulcer duration and pain while maintaining nutritional intake, and to prevent or diminish the frequency of recurrence (Kerr 2003).Treatment for recurrent oral ulcerations varies from topical steroid agents to thalidomide (Ghigliotti 1993). Topical anaesthetics play an important adjunctive role for pain control. In general, a direct application of topical therapy is adequate for mild cases of lesions that are easily reached, whereas patients with more severe aphthous ulcers or those with relatively inaccessible lesions generally require treatment with a corticosteroid‐containing oral medication. Unfortunately, topical therapy often produces inconsistent response rates and high rates of relapse. More recently, several case reports have noted successful remission of ulcer lesions with antiretroviral therapy (Dalmau 2007, Alegre 2007).

Several forms of topical treatment have been employed, including:

• Antiseptic mouthwashes such as chlorhexidine which is also available in gel and spray form for cases of secondary bacterial infection (Spyridon 2009).

• Topical corticosteroids such as clobetasol, fluocinonide, triamcinolone paste, and betamethasone mouthwash (Spyridon 2009).

• Local analgesics, mainly indicated for intolerable and intractable pain of chronic ulceration, such as with major ulcerations. Examples include lidocaine (available as 5% ointment/lozenges or 10% solution spray), Benzydamine hydrochloride (available as mouthwash or spray), and salicylates (available as oral gel or paste).

• Topical thalidomide (NIDCR 2008), topical sulphuric acid/phenolic solution(debacterol), Amlexanox (Aphthasol 5%) paste (Spyridon 2009).

Topical medications, such as antimicrobial mouthwashes and topical corticosteroids can achieve the primary goals but have not been shown to alter recurrence or remission rates (Barrons 2001). Severe ulcers and those not responding to topical therapy may require more aggressive management consisting of systemic corticosteroids, intralesional corticosteroids or a systemic immunomodulator, such as thalidomide (MacPhail 1992).Since there is no specific treatment of these aphthous ulcers and several agents are being employed, this review aims to determine the most effective topical treatment for HIV‐related oral aphthous ulcerations in adults.

Objectives

To evaluate the efficacy and side effects of topical agents used in the treatment of HIV‐related oral aphthous ulcers in adults.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials that evaluated the efficacy of any topical agent in treating HIV related oral aphthous ulcerations in adults.

Types of participants

HIV infected adults with one or more painful intraoral aphthous ulcers (we defined adults according to the Centre for Disease Control and Prevention (CDC) as being > 13years of age (Osmond 1998).

Types of interventions

Interventions comparing the efficacy of any topical agents versus another topical agent or placebo, including:

• Topical corticosteroids

• Topical thalidomide

• Antiseptic mouth washes such as chlorhexidine

• Any HAART regimen+ any topical treatment versus HAART regimen alone

Types of outcome measures

1. Healing of ulceration

2. Pain relief

3. Duration to heal oral ulcerations after initiation of treatment

4. Incidence and recurrence after healing of ulcers

5. Adverse effects of long‐term use of available topical agents

Search methods for identification of studies

See: HIV/AIDS Group methods used in reviews.                                                       

Electronic searches

The criteria used in searching included studies with relevant keywords and Medical Subject Heading (MeSH) terms. Search strategies used are recorded in Appendix 1:CENTRAL; Appendix 2:EMBASE; Appendix 3: PubMED (Dec 2010); and Appendix 4: PubMED (May 2011).

The following databases were searched for the period January 1980 to May 2011:

1. PUBMED

2. EMBASE

3. The Cochrane Central Register of Controlled Trials (CENTRAL)

4. AEGIS

5. ClinicalTrials.gov

Searching other resources  

We also searched the following conference proceedings for relevant abstracts:

1. The International AIDS Conference (IAC)

2. The Conference on Retroviruses and Opportunistic Infections (CROI)

3. The British HIV Association Conference (BHIVA)

4. The International Congress on Drug Therapy in HIV infection

5. The Interscience Conference on Antimicrobial Agents and Chemotherapy. (ICAAC Conference).

There was no language restriction in the searches. Hand searches of the reference lists of all pertinent reviews and studies found were also undertaken. Agencies, Organizations and Academic centres, as well as experts in the field of HIV management were also contacted to locate studies not included or found in the databases.   

Data collection and analysis

Two authors independently assessed the potentially eligible studies for inclusion. Only two studies appeared to meet the inclusion criteria but no full text report was available. No analysis was performed. We gave reasons for excluding potentially relevant trials in the characteristics of excluded studies.

Data extraction and management

We designed a data extraction form, but no data could be extracted as no studies were included in the review.

Assessment of risk of bias in included studies

Risk of bias could not be assessed as there were no included studies.

Results

Description of studies

There were no included studies.

Results of the search

A total of 233 abstracts were retrieved from the databases searched. Two authors working independently selected 25 abstracts as potentially eligible studies for inclusion but they were all excluded because non met the inclusion criteria. Ten of the studies evaluated systemic rather than topical treatment; 3 non‐RCTs, 6 case‐reports and 1 newsletter and others were conference abstracts with no full texts available.

Two studies from additional references that appeared to meet the inclusion criteria, are unpublished and all attempts to obtain the full text reports from the authors and organization were not successful. These 2 studies have been categorized as studies awaiting classification.

Included studies

No study was selected for inclusion due to insufficient reports on the 2 studies that appeared to meet the inclusion criteria.

Excluded studies

Fourteen of the studies selected and assessed to be potentially eligible for inclusion were excluded. See section on characteristics of excluded studies and Prisma flowchart (Figure 1).

1.

PRISMA flow chart

Risk of bias in included studies

Risk of bias could not be assessed since we could not obtain the full text artciles.

Effects of interventions

Effects of interventions could not be assessed.

Discussion

There were no included studies. This review has identified a gap and a need for well designed studies that will evaluate the effects of topical agents for treating HIV related aphthous ulcers. No objective discussion can be made on the efficacy and safety of topical treatments for HIV related aphthous ulcers.

Summary of main results

There were no included studies.

Overall completeness and applicability of evidence

Due to insufficient data available, no concrete description of relevance can be made based on the studies assessed.

Regarding the objective of this review and from the two studies that seemed to meet our inclusion criteria but with insufficient data, the evidence available is rather inconclusive.

Potential biases in the review process

We conducted a thorough and comprehensive search to identify any relevant studies. Two authors working independently examined the abstracts from the search output. We are unlikely to have missed any relevant study that met our inclusion criteria.

Authors' conclusions

Implications for practice.

No studies were included in this review. Therefore, we cannot make any recommendations for any specific topical treatment for HIV related oral aphthous ulcers in adults.

Implications for research.

There is a need for well‐designed studies to evaluate the efficacy of topical agents available for the treatment of HIV related oral ulcers.

Appendices

Appendix 1. CENTRAL search strategy

Database:       CLIB/CENTRAL (1996‐ 2010)

Date:               10 December 2010

ID	Search	Hits
#1	MeSH descriptor HIV Infections explode all trees	6327
#2	MeSH descriptor HIV explode all trees	2008
#3	hiv OR hiv‐1* OR hiv‐2* OR hiv1 OR hiv2 OR HIV INFECT* OR HUMAN IMMUNODEFICIENCY VIRUS OR HUMAN IMMUNEDEFICIENCY VIRUS OR HUMAN IMMUNE‐DEFICIENCY VIRUS OR HUMAN IMMUNO‐DEFICIENCY VIRUS OR HUMAN IMMUN* DEFICIENCY VIRUS OR ACQUIRED IMMUNODEFICIENCY SYNDROME OR ACQUIRED IMMUNEDEFICIENCY SYNDROME OR ACQUIRED IMMUNO‐DEFICIENCY SYNDROME OR ACQUIRED IMMUNE‐DEFICIENCY SYNDROME OR ACQUIRED IMMUN* DEFICIENCY SYNDROME	9653
#4	MeSH descriptor Lymphoma, AIDS‐Related, this term only	21
#5	MeSH descriptor Sexually Transmitted Diseases, Viral, this term only	18
#6	(#1 OR #2 OR #3 OR #4 OR #5)	9740
#7	MeSH descriptor Stomatitis, Aphthous explode all trees	148
#8	MeSH descriptor Oral Ulcer explode all trees	33
#9	aphthous:kw,ti,ab OR aphthae:kw,ti,ab OR canker sore*:ti,ab,kw OR periadenitis mucosa necrotica recurrens:kw,ti,ab OR oral ulcer*:kw,ti,ab OR oral stomatitis:kw,ti,ab OR oral aphthae:kw,ti,ab OR aphtous:kw,ti,ab OR oral mucositis:kw,ti,ab	2891
#10	(#7 OR #8 OR #9)	2891
#11	MeSH descriptor Administration, Topical explode all trees	11005
#12	MeSH descriptor Mouthwashes explode all trees	1725
#13	MeSH descriptor Thalidomide explode all trees	203
#14	MeSH descriptor Adrenal Cortex Hormones explode all trees	9642
#15	topical:kw,ti,ab OR mouthwash*:kw,ti,ab OR thalidomide:kw,ti,ab OR mouth wash*:kw,ti,ab OR mouth rinse*:kw,ti,ab OR mouthrinse*:kw,ti,ab OR corticosteroid*:kw,ti,ab OR corticoids:kw,ti,ab OR adrenal cortex hormones:kw,ti,ab	22842
#16	(#11 OR #12 OR #13 OR #15)	28652
#17	MeSH descriptor Antiretroviral Therapy, Highly Active, this term only	747
#18	MeSH descriptor Anti‐HIV Agents explode all trees	2839
#19	MeSH descriptor Antiviral Agents, this term only	2675
#20	MeSH descriptor AIDS Vaccines, this term only	244
#21	anti hiv OR antiretroviral* OR anti retroviral* OR aids vaccin*	4164
#22	(#17 OR #18 OR #19 OR #20 OR #21)	7178
#23	(#16 OR #22)	35559
#24	(#6 AND #10 AND #23)	25
#25	(#6 AND #10 AND #23), from 1996 to 2010	18

Database:                 CENTRAL (1980‐1995)

Issue Searched:     The Cochrane Library, 2011 Issue 2

Date:                          6 May 2011

ID	Search	Hits
#1	MeSH descriptor HIV Infections explode all trees	6562
#2	MeSH descriptor HIV explode all trees	2104
#3	hiv OR hiv‐1* OR hiv‐2* OR hiv1 OR hiv2 OR HIV INFECT* OR HUMAN IMMUNODEFICIENCY VIRUS OR HUMAN IMMUNEDEFICIENCY VIRUS OR HUMAN IMMUNE‐DEFICIENCY VIRUS OR HUMAN IMMUNO‐DEFICIENCY VIRUS OR HUMAN IMMUN* DEFICIENCY VIRUS OR ACQUIRED IMMUNODEFICIENCY SYNDROME OR ACQUIRED IMMUNEDEFICIENCY SYNDROME OR ACQUIRED IMMUNO‐DEFICIENCY SYNDROME OR ACQUIRED IMMUNE‐DEFICIENCY SYNDROME OR ACQUIRED IMMUN* DEFICIENCY SYNDROME	10163
#4	MeSH descriptor Lymphoma, AIDS‐Related, this term only	21
#5	MeSH descriptor Sexually Transmitted Diseases, Viral, this term only	20
#6	(#1 OR #2 OR #3 OR #4 OR #5)	10251
#7	MeSH descriptor Stomatitis, Aphthous explode all trees	154
#8	MeSH descriptor Oral Ulcer explode all trees	35
#9	aphthous:kw,ti,ab OR aphthae:kw,ti,ab OR canker sore*:ti,ab,kw OR periadenitis mucosa necrotica recurrens:kw,ti,ab OR oral ulcer*:kw,ti,ab OR oral stomatitis:kw,ti,ab OR oral aphthae:kw,ti,ab OR aphtous:kw,ti,ab OR oral mucositis:kw,ti,ab	2946
#10	(#7 OR #8 OR #9)	2946
#11	MeSH descriptor Administration, Topical explode all trees	11295
#12	MeSH descriptor Mouthwashes explode all trees	1787
#13	MeSH descriptor Thalidomide explode all trees	225
#14	MeSH descriptor Adrenal Cortex Hormones explode all trees	9887
#15	topical:kw,ti,ab OR mouthwash*:kw,ti,ab OR thalidomide:kw,ti,ab OR mouth wash*:kw,ti,ab OR mouth rinse*:kw,ti,ab OR mouthrinse*:kw,ti,ab OR corticosteroid*:kw,ti,ab OR corticoids:kw,ti,ab OR adrenal cortex hormones:kw,ti,ab	23341
#16	(#11 OR #12 OR #13 OR #15)	29321
#17	MeSH descriptor Antiretroviral Therapy, Highly Active, this term only	797
#18	MeSH descriptor Anti‐HIV Agents explode all trees	2949
#19	MeSH descriptor Antiviral Agents, this term only	2800
#20	MeSH descriptor AIDS Vaccines, this term only	257
#21	anti hiv OR antiretroviral* OR anti retroviral* OR aids vaccin*	4443
#22	(#17 OR #18 OR #19 OR #20 OR #21)	7591
#23	(#16 OR #22)	36630
#24	(#6 AND #10 AND #23)	25
#25	(#6 AND #10 AND #23), from 1980 to 1995	7

Appendix 2. EMBASE search strategy

Database:       EMBASE (1996 – 2010)

Date:               2 December 2010

No.	Query	Results	Date
#10	#4 AND #7 AND [embase]/lim AND [1‐1‐1996]/sd NOT [2‐12‐2010]/sd	36	2 Dec 2010
#8	#4 AND #7	47	2 Dec 2010
#7	#5 OR #6	1371582	2 Dec 2010
#6	'human immunodeficiency virus vaccine'/de OR 'human immunodeficiency virus vaccine' OR 'anti human immunedeficiency':ti OR 'anti human immunedeficiency':ab OR 'anti human immunodeficiency':ti OR 'anti human immunodeficiency':ab OR 'anti human immuno‐deficiency':ti OR 'anti human immuno‐deficiency':ab OR 'anti human immune‐deficiency':ti OR 'anti human immune‐deficiency':ab OR 'anti acquired immune‐deficiency':ti OR 'anti acquired immune‐deficiency':ab OR 'anti acquired immunedeficiency':ti OR 'anti acquired immunedeficiency':ab OR 'anti acquired immunodeficiency':ti OR 'anti acquired immunodeficiency':ab OR 'anti acquired immuno‐deficiency':ti OR 'anti acquired immuno‐deficiency':ab OR 'anti hiv':ti OR 'anti hiv':ab OR antiretrovir*:ti OR antiretrovir*:ab OR 'anti retroviral':ti OR 'anti retroviral':ab OR 'anti retrovirals':ti OR 'anti retrovirals':ab OR 'anti retrovirus':ti OR 'anti retrovirus':ab OR haart:ti OR haart:ab OR 'aids vaccine':ti OR 'aids vaccine':ab OR 'aids vaccines':ti OR 'aids vaccines':ab OR 'anti human immunodeficiency virus agent'/de OR 'anti human immunodeficiency virus agent' OR 'antiretrovirus agent'/de OR 'antiretrovirus agent' OR 'antivirus agent'/de OR 'antivirus agent' OR 'highly active antiretroviral therapy'/de OR 'highly active antiretroviral therapy'	494404	2 Dec 2010
#5	'topical drug administration'/de OR 'topical drug administration' OR 'topical'/de OR topical OR 'mouthwash'/de OR mouthwash OR 'mouth rinse'/de OR 'mouth rinse' OR 'mouth rinses'/de OR 'mouth rinses' OR 'mouth wash'/de OR 'mouth wash' OR 'mouth washes'/de OR 'mouth washes' OR 'mouthrinse'/de OR mouthrinse OR 'mouthrinses'/de OR mouthrinses OR 'mouthwashes'/de OR mouthwashes OR 'thalidomide'/de OR thalidomide OR 'adrenal steroid'/de OR 'adrenal steroid' OR 'corticoid'/de OR corticoid OR 'corticosteroid'/de OR corticosteroid OR corticosteroids OR 'corticotherapy'/de OR corticotherapy OR corticoids	959246	2 Dec 2010
#4	#1 AND #2 AND #3	56	2 Dec 2010
#3	'aphthous stomatitis'/de OR 'aphthous stomatitis' OR 'mouth ulcer'/de OR 'mouth ulcer' OR 'mouth ulcers' OR 'mouth ulceration'/de OR 'mouth ulceration' OR 'mouth ulcerations' OR 'buccal ulcer'/de OR 'buccal ulcer' OR 'oral ulcer'/de OR 'oral ulcer' OR 'oral ulcers' OR 'oral ulceration'/de OR 'oral ulceration' OR 'oral ulcerations' OR aphthous OR aphtous OR aphthosa OR aphthosis OR aphthea OR 'canker sore' OR 'canker sores'	9875	2 Dec 2010
#2	random*:ti OR random*:ab OR factorial*:ti OR factorial*:ab OR cross?over*:ti OR cross?over*:ab OR crossover*:ti OR crossover*:ab OR placebo*:ti OR placebo*:ab OR (doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab) OR (singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab) OR assign*:ti OR assign*:ab OR allocat*:ti OR allocat*:ab OR volunteer*:ti OR volunteer*:ab OR 'crossover procedure'/exp OR 'crossover procedure'/de OR 'crossover procedure' OR 'double‐blind procedure'/exp OR 'double‐blind procedure'/de OR 'double‐blind procedure' OR 'single‐blind procedure'/exp OR 'single‐blind procedure'/de OR 'single‐blind procedure' OR 'randomized controlled trial'/exp OR 'randomized controlled trial'/de OR 'randomized controlled trial'	1037662	2 Dec 2010
#1	'human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection'/de OR 'human immunodeficiency virus infection' OR 'human immunodeficiency virus'/exp OR 'human immunodeficiency virus'/de OR 'human immunodeficiency virus' OR hiv:ti OR hiv:ab OR 'hiv‐1':ti OR 'hiv‐1':ab OR 'hiv‐2':ti OR 'hiv‐2':ab OR 'human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab OR 'human immuno‐deficiency virus':ti OR 'human immuno‐deficiency virus':ab OR 'human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab OR 'human immune‐deficiency virus':ti OR 'human immune‐deficiency virus':ab OR 'acquired immune‐deficiency syndrome':ti OR 'acquired immune‐deficiency syndrome':ab OR 'acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab OR 'acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab OR 'acquired immuno‐deficiency syndrome':ti OR 'acquired immuno‐deficiency syndrome':ab	325291	2 Dec 2010

Database:     EMBASE (1980 ‐ 1995)

 Date:              6 May 2011

No.	Query	Results	Date
#9	#4 AND #7 AND [humans]/lim AND [embase]/lim AND [1‐1‐1980]/sd NOT [31‐12‐1995]/sd	4	6 May 2011
#8	#4 AND #7	50	6 May 2011
#7	#5 OR #6	1413499	6 May 2011
#6	'human immunodeficiency virus vaccine'/de OR 'human immunodeficiency virus vaccine' OR 'anti human immunedeficiency':ti OR 'anti human immunedeficiency':ab OR 'anti human immunodeficiency':ti OR 'anti human immunodeficiency':ab OR 'anti human immuno‐deficiency':ti OR 'anti human immuno‐deficiency':ab OR 'anti human immune‐deficiency':ti OR 'anti human immune‐deficiency':ab OR 'anti acquired immune‐deficiency':ti OR 'anti acquired immune‐deficiency':ab OR 'anti acquired immunedeficiency':ti OR 'anti acquired immunedeficiency':ab OR 'anti acquired immunodeficiency':ti OR 'anti acquired immunodeficiency':ab OR 'anti acquired immuno‐deficiency':ti OR 'anti acquired immuno‐deficiency':ab OR 'anti hiv':ti OR 'anti hiv':ab OR antiretrovir*:ti OR antiretrovir*:ab OR 'anti retroviral':ti OR 'anti retroviral':ab OR 'anti retrovirals':ti OR 'anti retrovirals':ab OR 'anti retrovirus':ti OR 'anti retrovirus':ab OR haart:ti OR haart:ab OR 'aids vaccine':ti OR 'aids vaccine':ab OR 'aids vaccines':ti OR 'aids vaccines':ab OR 'anti human immunodeficiency virus agent'/de OR 'anti human immunodeficiency virus agent' OR 'antiretrovirus agent'/de OR 'antiretrovirus agent' OR 'antivirus agent'/de OR 'antivirus agent' OR 'highly active antiretroviral therapy'/de OR 'highly active antiretroviral therapy'	515712	6 May 2011
#5	'topical drug administration'/de OR 'topical drug administration' OR 'topical' OR 'topical'/de OR topical OR 'mouthwash' OR 'mouthwash'/de OR mouthwash OR 'mouth rinse'/de OR 'mouth rinse' OR 'mouth rinses'/de OR 'mouth rinses' OR 'mouth wash'/de OR 'mouth wash' OR 'mouth washes'/de OR 'mouth washes' OR 'mouthrinse' OR 'mouthrinse'/de OR mouthrinse OR 'mouthrinses' OR 'mouthrinses'/de OR mouthrinses OR 'mouthwashes' OR 'mouthwashes'/de OR mouthwashes OR 'thalidomide' OR 'thalidomide'/de OR thalidomide OR 'adrenal steroid'/de OR 'adrenal steroid' OR 'corticoid' OR 'corticoid'/de OR corticoid OR 'corticosteroid' OR 'corticosteroid'/de OR corticosteroid OR corticosteroids OR 'corticotherapy' OR 'corticotherapy'/de OR corticotherapy OR corticoids	982666	6 May 2011
#4	#1 AND #2 AND #3	59	6 May 2011
#3	'aphthous stomatitis'/de OR 'aphthous stomatitis' OR 'mouth ulcer'/de OR 'mouth ulcer' OR 'mouth ulcers' OR 'mouth ulceration'/de OR 'mouth ulceration' OR 'mouth ulcerations' OR 'buccal ulcer'/de OR 'buccal ulcer' OR 'oral ulcer'/de OR 'oral ulcer' OR 'oral ulcers' OR 'oral ulceration'/de OR 'oral ulceration' OR 'oral ulcerations' OR aphthous OR aphtous OR aphthosa OR aphthosis OR aphthea OR 'canker sore' OR 'canker sores'	10277	6 May 2011
#2	random*:ti OR random*:ab OR factorial*:ti OR factorial*:ab OR cross?over*:ti OR cross?over*:ab OR crossover*:ti OR crossover*:ab OR placebo*:ti OR placebo*:ab OR (doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab) OR (singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab) OR assign*:ti OR assign*:ab OR allocat*:ti OR allocat*:ab OR volunteer*:ti OR volunteer*:ab OR 'crossover procedure'/exp OR 'crossover procedure'/de OR 'crossover procedure' OR 'double‐blind procedure'/exp OR 'double‐blind procedure'/de OR 'double‐blind procedure' OR 'single‐blind procedure'/exp OR 'single‐blind procedure'/de OR 'single‐blind procedure' OR 'randomized controlled trial'/exp OR 'randomized controlled trial'/de OR 'randomized controlled trial'	1086435	6 May 2011
#1	'human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection'/de OR 'human immunodeficiency virus infection' OR 'human immunodeficiency virus'/exp OR 'human immunodeficiency virus'/de OR 'human immunodeficiency virus' OR hiv:ti OR hiv:ab OR 'hiv‐1':ti OR 'hiv‐1':ab OR 'hiv‐2':ti OR 'hiv‐2':ab OR 'human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab OR 'human immuno‐deficiency virus':ti OR 'human immuno‐deficiency virus':ab OR 'human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab OR 'human immune‐deficiency virus':ti OR 'human immune‐deficiency virus':ab OR 'acquired immune‐deficiency syndrome':ti OR 'acquired immune‐deficiency syndrome':ab OR 'acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab OR 'acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab OR 'acquired immuno‐deficiency syndrome':ti OR 'acquired immuno‐deficiency syndrome':ab	348181	6 May 2011

Appendix 3. PUBMED search strategy

Database:     PubMed (1996 – 2010)

Date:              3 December 2010 

Search	Most Recent Queries	Time	Result
#10	Search #5 AND #8 Limits: Publication Date from 1996/01/01 to 2010/12/03	03:59:49	105
#9	Search #5 AND #8	03:58:42	152
#8	Search #6 OR #7	03:58:19	454169
#7	Search topical[tiab] OR administration, topical[mh] OR mouthwashes[mh] OR mouthwashes[tiab] OR mouthwash[tiab] OR thalidomide[mh] OR thalidomide[tiab] OR corticosteroids[tiab] OR mouth rinse[tiab] OR mouth rinses[tiab] OR mouth wash[tiab] OR mouth washes[tiab] OR mouthrinse[tiab] OR mouthrinses[tiab] OR corticosteroid[tiab] OR corticosteroids[tiab] OR adrenal cortex hormones[mh] OR adrenal cortex hormones[tiab] OR corticoid[tiab] OR corticoids[tiab]	03:58:08	346527
#6	Search Antiretroviral Therapy, Highly Active[MeSH] OR Anti‐Retroviral Agents[MeSH] OR Antiviral Agents[MeSH:NoExp] OR ((anti) AND (hiv[tw])) OR antiretroviral*[tw] OR ((anti) AND (retroviral*[tw])) OR HAART[tw] OR ((anti) AND (acquired immunodeficiency[tw])) OR ((anti) AND (acquired immunedeficiency[tw])) OR ((anti) AND (acquired immuno‐deficiency[tw])) OR ((anti) AND (acquired immune‐deficiency[tw])) OR ((anti) AND (acquired immun*) AND (deficiency[tw]))	03:57:55	110728
#5	Search #1 AND #2 AND #4	03:57:16	209
#4	Search stomatitis, aphthous[mh] OR aphthous stomatitis[tiab] OR aphthous stomatitides[tiab] OR aphthae[tiab] OR canker sore[tiab] OR canker sores[tiab] OR periadenitis mucosa necrotica recurrens[tiab] OR oral ulcer[mh] OR oral ulcers[tiab] OR oral ulcer[tiab] OR mouth ulcer[tiab] OR mouth ulcers[tiab] OR oral ulceration[tiab] OR oral ulcerations[tiab] OR oral stomatitis[tiab] OR oral aphthae[tiab] OR aphthous ulceration[tiab] OR aphthous ulcerations[tiab] OR aphtous[tiab] OR oral mucositis[tiab] OR aphthous ulcer[tiab] OR aphthous ulcers[tiab]	03:56:49	6231

Appendix 4. PUBMED search strategy

Database:     PubMed (1980 – 1995)

Date:              6 May 2011

Search	Most Recent Queries	Time	Result
#9	Search #4 AND #7 Limits: Publication Date from 1980/01/01 to 1995/12/31	02:47:23	47
#8	Search #4 AND #7	02:46:46	154
#7	Search #5 OR #6	02:46:37	463960
#6	Search topical[tiab] OR administration, topical[mh] OR mouthwashes[mh] OR mouthwashes[tiab] OR mouthwash[tiab] OR thalidomide[mh] OR thalidomide[tiab] OR corticosteroids[tiab] OR mouth rinse[tiab] OR mouth rinses[tiab] OR mouth wash[tiab] OR mouth washes[tiab] OR mouthrinse[tiab] OR mouthrinses[tiab] OR corticosteroid[tiab] OR corticosteroids[tiab] OR adrenal cortex hormones[mh] OR adrenal cortex hormones[tiab] OR corticoid[tiab] OR corticoids[tiab]	02:46:25	352474
#5	Search Antiretroviral Therapy, Highly Active[MeSH] OR Anti‐Retroviral Agents[MeSH] OR Antiviral Agents[MeSH:NoExp] OR ((anti) AND (hiv[tw])) OR antiretroviral*[tw] OR ((anti) AND (retroviral*[tw])) OR HAART[tw] OR ((anti) AND (acquired immunodeficiency[tw])) OR ((anti) AND (acquired immunedeficiency[tw])) OR ((anti) AND (acquired immuno‐deficiency[tw])) OR ((anti) AND (acquired immune‐deficiency[tw])) OR ((anti) AND (acquired immun*) AND (deficiency[tw]))	02:46:03	114690
#4	Search #1 AND #2 AND #3	02:45:44	212
#3	Search stomatitis, aphthous[mh] OR aphthous stomatitis[tiab] OR aphthous stomatitides[tiab] OR aphthae[tiab] OR canker sore[tiab] OR canker sores[tiab] OR periadenitis mucosa necrotica recurrens[tiab] OR oral ulcer[mh] OR oral ulcers[tiab] OR oral ulcer[tiab] OR mouth ulcer[tiab] OR mouth ulcers[tiab] OR oral ulceration[tiab] OR oral ulcerations[tiab] OR oral stomatitis[tiab] OR oral aphthae[tiab] OR aphthous ulceration[tiab] OR aphthous ulcerations[tiab] OR aphtous[tiab] OR oral mucositis[tiab] OR aphthous ulcer[tiab] OR aphthous ulcers[tiab]	02:45:24	6386
#2	Search (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])	02:45:07	2384891
#1	Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv‐1*[tw] OR hiv‐2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno‐deficiency virus[tw] OR human immune‐deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno‐deficiency syndrome[tw] OR acquired immune‐deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "sexually transmitted diseases, viral"[MH:noexp]	02:44:46	271925

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Alexander 1997	Oesophageal ulcers and Non‐Topical ( Oral) treatment
Herranz 2000	Not a controlled trial, No randomisation
Hoy 1991	Oral (systemic) treatment
Jacobson 1997	Non‐Topical ( Oral) treatment
Jacobson 1999	Oesophageal ulcers and Non‐Topical ( Oral) treatment
Jacobson 2001	Non‐Topical ( Oral) treatment
Kulkarni 2002	Non‐Topical ( Oral) treatment
MacPhail 1992	Non‐RCT
Paterson 1995	Non‐Topical ( Oral) treatment
Ramirez‐Amador 1999	Non‐Topical ( Oral) treatment
Randall 1995	Non‐Topical ( Oral) treatment
Thompson 1995	Non‐Topical ( Oral) treatment
Vargas 1998	No randomisation
Youle 1989	Not a controlled trial, No randomisation

Characteristics of studies awaiting assessment [ordered by study ID]

Gordon 2003.

Methods	Double‐blind, randomised, placebo‐controlled trial
Participants	Patients with HIV infection
Interventions	20mg topical thalidomide (ointment)
Outcomes	Ulcer healing and pain relief
Notes	We did not find any full text article for to assess the study eligibility

NIDCR 2008.

Methods	Randomised controlled trial
Participants	HIV infected adults with one or more chronic, painful intraoral lesions
Interventions	Topical thalidomide
Outcomes	Healing, pain, and the incidence of side effects will be assessed
Notes	Location of study; United states.

Differences between protocol and review

The age was changed from >15 years to >13 years in the type of participants, motivated by the definition of adults by the Center for Disease Control (CDC).

Contributions of authors

Kuteyi Teslim and Charles Okwundu contributed to the protocol development, part of the literature search, assessment of potentially eligible studies for inclusion and write up of review.

Sources of support

Internal sources

• South African Cochrane Centre, Medical Research Council, South Africa.

• HIV/AIDS Mentoring Programme, South Africa.

External sources

• No sources of support supplied

Declarations of interest

No known conflict of interest.

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