Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children

 

Abstract

Background

Oral candidiasis (OC) associated with human immunodeficiency virus (HIV) infection occurs commonly and recurs frequently, often presenting as an initial manifestation of the disease. Left untreated, these lesions contribute considerably to the morbidity associated with HIV infection. Interventions aimed at preventing and treating HIV-associated oral candidal lesions form an integral component of maintaining the quality of life for affected individuals.

Objectives

To determine the effects of any intervention in preventing or treating OC in children and adults with HIV infection.

Search methods

The search strategy was based on that of the Cochrane HIV/AIDS Review Group. The following electronic databases were searched for randomised controlled trials for the years 1982 to 2005: Medline, AIDSearch, EMBASE and CINAHL. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, and the Cochrane Central Register of Controlled Trials (CENTRAL) were also searched through May 2005. The abstracts of relevant conferences, including the International Conferences on AIDS and the Conference on Retroviruses and Opportunistic Infections, as indexed by AIDSLINE, were also reviewed. The strategy was iterative, in that references of included studies were searched for additional references. All languages were included.

The updated database search was done for the period 2005 up to 2009. The following databases were searched: Medline, EMBASE, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library. AIDSearch was not searched for the updated search as it ceased publication during 2008.

Selection criteria

Randomised controlled trials (RCTs) of palliative, preventative or curative therapy were considered, irrespective of whether the control group received a placebo. Participants were HIV positive adults and children.

Data collection and analysis

Two authors independently assessed the methodological quality of the trials and extracted data. Study authors were contacted for additional data where necessary.

Main results

For the first publication of the review in 2006, forty studies were retrieved. Twenty eight trials (n=3225) met inclusion criteria. During the update search for the review a, further six studies were identified. Of these, five met the inclusion criteria and were included in the review. The review now includes 33 studies (n=3445): 22 assessing treatment and 11 assessing prevention of oropharyngeal candidiasis. Six studies were done in developing countries, 16 in the United States of America and the remainder in Europe.

Treatment
Treatment was assessed in the majority of trials looking at both clinical and mycological cures. In the majority of comparisons there was only one trial. Compared to nystatin, fluconazole favoured clinical cure in adults (1 RCT; n=167; RR 1.69; 95% CI 1.27 to 2.23). There was no difference with regard to clinical cure between fluconazole compared to ketoconazole (2 RCTs; n=83; RR 1.27; 95% CI 0.97 to 1.66), itraconazole (2 RCTs; n=434; RR 1.05; 95% CI 0.94 to 1.16), clotrimazole (2 RCTs; n=358; RR 1.14; 95% CI 0.92 to 1.42) or posaconazole (1 RCT; n=366; RR1.32; 95% CI 0.36 to 4.83). Two trials compared different dosages of fluconazole with no difference in clinical cure. When compared with clotrimazole, both fluconazole (2 RCTs; n=358; RR 1.47; 95% CI 1.16 to 1.87) and itraconazole (1 RCT; n=123; RR 2.20; 95% CI 1.43 to3.39) proved to be better for mycological cure. Both gentian violet (1 RCT; n=96; RR 5.28; 95% CI 1.23 to 22.55) and ketoconazole (1 RCT; n=92; RR 5.22; 95% CI 1.21 to 22.53) were superior to nystatin in bringing about clinical cure. A single trial compared gentian violet with lemon juice and lemon grass with no significant difference in clinical cure between the groups.

Prevention
Successful prevention was defined as the prevention of a relapse while receiving prophylaxis. Fluconazole was compared with placebo in five studies (5 RCTs; n=599; RR 0.61; 95% CI 0.5 to 0.74) and with no treatment in another (1 RCT; n=65; RR 0.16; 95% CI 0.08 to 0.34). In both instances the prevention of clinical episodes was favoured by fluconazole. Comparing continuous fluconazole treatment with intermittent treatment (2 RCTs; n=891; RR 0.65; 95% CI 0.23 to 1.83), there was no significant difference between the two treatment arms. Chlorhexidine was compared with normal saline in a single study with no significant difference between the treatment arms.

Authors' conclusions

Five new studies were added to the review, but their results do not alter the final conclusion of the review.

Implications for practice
Due to there being only one study in children, it is not possible to make recommendations for treatment or prevention of OC in children. Amongst adults, there were few studies per comparison. Due to insufficient evidence, no conclusion could be made about the effectiveness of clotrimazole, nystatin, amphotericin B, itraconazole or ketoconazole with regard to OC prophylaxis. In comparison to placebo, fluconazole is an effective preventative intervention. However, the potential for resistant Candida organisms to develop, as well as the cost of prophylaxis, might impact the feasibility of implementation. No studies were found comparing fluconazole with other interventions. The direction of findings suggests that ketoconazole, fluconazole, itraconazole and clotrimazole improved the treatment outcomes.

Implications for research
It is encouraging that low-cost alternatives are being tested, but more research needs to be on in this area and on interventions like gentian violet and other less expensive anti-fungal drugs to treat OC. More well-designed treatment trials with larger samples are needed to allow for sufficient power to detect differences in not only clinical, but also mycological, response and relapse rates. There is also a strong need for more research to be done on the treatment and prevention of OC in children as it is reported that OC is the most frequent fungal infection in children and adolescents who are HIV positive. More research on the effectiveness of less expensive interventions also needs to be done in resource-poor settings. Currently few trials report outcomes related to quality of life, nutrition, or survival. Future researchers should consider measuring these when planning trials. Development of resistance remains under-studied and more work must be done in this area. It is recommended that trials be more standardised and conform more closely to CONSORT.

 

Plain language summary

Interventions for the prevention and management of oral thrush associated with HIV infection in adults and children

Oral candidiasis (thrush) associated with human immunodeficiency virus (HIV) infection occurs commonly and recurs frequently, often presenting as an initial manifestation of the disease. Interventions aimed at preventing and treating HIV-associated oral thrush form an integral component of maintaining the quality of life for affected individuals. This review evaluated the effects of interventions in preventing or treating oral thrush in children and adults with HIV infection. Thirty three trials (n=3445) were included. Twenty two trials investigated treatment and eleven trials investigate prevention. There was no difference with regard to clinical cure between fluconazole compared to ketoconazole, itraconazole, clotrimazole and posaconazole. Fluconazole, gentian violet and ketoconazole were superior to nystatin. Compared to placebo and no treatment, fluconazole was effective in preventing clinical episodes from occurring. Continuous fluconazole was better than intermittent treatment. Insufficient evidence was found to come to any conclusion about the effectiveness of clotrimazole, nystatin, amphotericin B, itraconazole, ketoconazole or chlorhexidine with regard to OC prophylaxis.

 

摘要

背景

患有HIV 的成人以及孩童感染(口咽)念珠菌症的處理和干預

Oral candidiasis (OC) 口腔的念珠菌症與人類免疫缺乏病毒感染相關且常常復發.而且經常是人類免疫缺乏病毒(HIV)感染的最早表現徵狀.如不治療常會引起人類免疫缺乏病毒感染的病患死亡.我們干預的目標在於預防和治療人類免疫缺乏病毒(HIV)引起的口腔的念珠菌症以及維持病人的生活品質。

目標

在人類免疫缺乏病毒感染的病人合併口腔念珠菌症時評估任何治療方式的療效及預防的效果。

搜尋策略

文獻搜尋的策略主要是以 “HIV/AIDS” 為搜索字在Cochrane Review Group搜尋.以下網路搜尋而來的文獻是在1982到2005 的 Medline; AIDSearch; EMBASE and CINAHL裡頭的隨機控制試驗找出來的.同時我們也尋找Cochrane Database 和Effectiveness and the Cochrane Central Register of Controlled Trials (CENTRAL)裡頭自2005/5 的回顧文章.摘要裡面參考目錄,主要是以AIDSLINE為搜尋字串在International Conferences on AIDS and the Conference on Retroviruses and Opportunistic Infections尋找.因此文章裡面的參考資料亦有包含在搜尋範圍裡頭.所有的語言都有包括在裡面.

選擇標準

不論控制組是否有對照組作對照，Randomised controlled trials (RCTs)在姑息性(Palliative),預防性(Preventive)和治癒性(Curative)治療都在選擇範圍之類。

資料收集與分析

兩位作者獨立地找尋資料和解讀分析資料.如果需要時,還會和文章作者聯絡來取得額外的資料.

主要結論

四個試驗正在發展中國家進行,而十一個試驗正在美國進行當中.一共有二十八個試驗(病人數 = 3225)被選入.有十九個試驗是檢驗治療而九個試驗是從事避免口腔念珠菌感染方面.有一個試驗是做在孩童中fluconazole 及ketoconazole的比較.有十八個試驗有報告病人的CD4細胞 數量.我們選入的試驗中沒有一個提到HAART或是抗反轉錄病毒藥物在治療咽念珠菌感染方面的影響.大多數的試驗中都有提到在臨床或是黴菌的治療成效。只有一個試驗提到比對.和nystatin相比, fluconazole在成人中較有臨床上的治癒 (1 RCT; n = 167; RR 1.69; 95% CI 1.27 to 2.23).以Ketonazole和fluconazole相比,沒有臨床上治療的差異 (2 RCTs; n = 83; RR 1.27; 95% CI 0.97 to 1.66), ketonazole和itraconazole 相比結果是(2 RCTs; n = 434; RR 1.05; 95% CI 0.94 to 1.16). Ketonazole和clotrimazole結果是 (2 RCTs; n = 358; RR 1.14; 95% CI 0.92 to 1.42). 和clotrimazole相比, fluconazole (2 RCTs; n = 358; RR 1.47; 95% CI 1.16 to 1.87)以及itraconazole (1 RCT; n = 123; RR 2.20; 95% CI 1.43 to3.39) 都證明有較佳的黴菌療效.龍膽紫(1 RCT; n = 96; RR 5.28; 95% CI 1.23 to 22.55) 和ketoconazole (1 RCT; n = 92; RR 5.22; 95% CI 1.21 to 22.53)跟nystatin相較之下, 均有較好的治癒效果.成功的預防效果被定義為在接受預防治療時病人沒有復發感染.在一個試驗中,以Fluconazole治療(5 RCTs; n = 599; RR 0.61; 95% CI 0.5 to 0.74) 和以安慰劑治療1 RCT; n = 65; RR 0.16; 95% CI 0.08 to 0.34) 相比下, fluconazole有比較好的療效.比較連續的和間斷性的fluconazole治療(1 RCT; n = 62; RR 0.37; 95% CI 0.15 to 0.92), 結果是以連續的fulconazole治療較佳.

作者結論

在孩童感染口腔念珠菌的治療方面,因為只有一個試驗提到因此難以提供治療建議.在成人的治療方面,有幾個試驗經由比較提供建議.因為證據不足因此不能提供clotrimazole, nystatin, amphotericin B, itraconazole or ketoconazole在預防口腔念珠菌治療方面建議.相較於安慰劑, fluconazole是一個有效的預防藥劑.然而,在念珠菌可能產生抗藥性以及預防用藥的花費會影響我們治療的考量. 沒有試驗做fluconazole和其他藥物的比較. 研究結果建議ketoconazole, fluconazole, itraconazole and clotrimazole可以增加治療效果. 對於gentian violet 以及其他較花費較便宜的抗黴菌藥物目前有急迫的需要的. 為了不只在臨床上且在黴菌的療效及復發率上看出差別，我們需要更多設計良好的試驗與更多的病人數。有報導在HIV陽性的兒童與青少年，口腔念珠菌感染是最常見的黴菌感染，因此在治療與預防兒童口腔念珠菌上對於更多的研究有更強烈的需求。對較不昂貴的治療,在資源匱乏的區域是需要有更多研究並且需要完成。少量試驗當前報告結果與生活水平、營養, 或生存有關。未來的研究者在計劃試驗時應考量這些指標。抗藥性的發生仍然被低估，且需要投入更多的工作。目前建議這些試驗需要標準化且更接近CONSORT規章，因為這可以增近研究且臨床工作。

翻譯人

本摘要由臺北榮民總醫院簡志翔翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

在HIV感染的成人與小孩預防及治療鵝口瘡：因HIV感染引起的口腔念珠菌(鵝口瘡)常常發生且常復發，也常是這種疾病一開始的表徵。干預方面主要是在防止並且處理HIV 伴隨而來的口鵝口瘡且維護生活水平。這個回顧評估了在HIV感染的小孩及成人預防或治療鵝口瘡的效果。共有二十八個試驗納入，其中19個試驗調查治療而另外九個調查預防。療效在FLUCONAZOLE，KETOCONAZOLE，ITRACONAZOLE或CLOTRICONAZOLE之間是沒有差別的。FLUCONAZOLE，龍膽紫與KETOCONAZOLE均較NYSTATIN優越。與安慰劑和沒有治療比較, fluconazole 有效地防止臨床感染的發生。連續的fluconazole 比斷斷續續的治療好。沒有足夠的證據可以呈現CLOTRICONAZOLE，NYSTATIN，AMPHOTERICIN B，ITRACONAZOLE或KETOCONAZOLE在口腔念珠菌預防上面的效果。