Primary prevention of invasive cryptococcal disease using fluconazole prophylaxis in HIV infected Ugandans

在非洲和资源丰富的国家，艾滋病的最初阶段非常相似，但在艾滋病发展之后，大多数非洲国家的存活率很低。造成这种差异的原因是治疗艾滋病毒感染的药物（抗逆转录病毒疗法）供应不足，以及对机会性感染的诊断和治疗不足。尽管国际社会为增加非洲获得抗逆转录病毒药物作出了重大努力，但有限的基础设施意味着获得抗逆转录病毒药物仍然受到严重限制：即使在可以获得抗逆转录病毒药物的地区，也经常有等候名单。因此，预防艾滋病毒感染者的机会性感染是一个高度优先事项，因为它允许在获得抗逆转录病毒治疗之前健康生存。侵袭性隐球菌病是非洲和其他热带地区艾滋病毒/艾滋病患者罹患危及生命疾病的主要原因之一，可能导致高达20%的死亡。已确定的隐球菌病治疗困难且费用昂贵；在资源有限和无法获得药物的国家，该病往往是一种晚期诊断。预防隐球菌和其他真菌疾病可对非洲的发病率和死亡率产生相当大的影响，特别是对那些无法获得或正在等待抗逆转录病毒治疗的人。美国和欧洲的研究表明，经常使用抗真菌药物氟康唑可以预防隐球菌和其他真菌疾病。在非洲还没有进行过类似的研究，但热带地区隐球菌病发病率较高，这意味着对发病率和死亡率的影响可能更大。非专利氟康唑现在在非洲可以免费廉价地获得，这意味着使用氟康唑预防隐球菌病的战略变得越来越有吸引力，特别是在现有疾病难以治疗的情况下。这项研究已经开始与TASO（艾滋病支持组织）合作，TASO是乌干达主要的艾滋病毒护理组织，669名参与者参加了一项双盲研究，比较氟康唑与安慰剂的疗效和安全性，测量隐球菌疾病和死亡率。然而，由于在研究地点广泛使用抗逆转录病毒治疗以及筛查出风险最大的参与者，隐球菌疾病的发病率低于预期。我们现在正在寻求扩展这项研究，允许再入组870名患者，从而确保这项研究足够强大，使我们能够对这种干预的益处做出明确的结论。

The initial stages of HIV disease are very similar in Africa and resource rich countries, but after AIDS develops, survival is poor in most African countries. This difference is attributed to poor availability of the drugs for treatment of HIV infection (antiretroviral therapy, ART) and inadequate diagnosis and treatment of opportunistic infections. Although there have been major international efforts to increase access to anti-retroviral drugs in Africa, limited infrastructure means that access to ART is still severely restricted: even in areas where ART is available, there are often waiting lists. Prevention of opportunistic infections in the HIV infected is therefore a high priority as it permits healthy survival until ART becomes available. Invasive cryptococcal disease is one of the major causes of life-threatening illness in HIV/AIDS patients in Africa and other parts of the tropics and may cause up to 20% of deaths. Established cryptococcal disease is difficult and costly to treat; it is often a terminal diagnosis in countries with limited resources and access to drugs. Prevention of cryptococcal and other fungal diseases could have a considerable impact upon morbidity and mortality in Africa, especially in those unable to access or who are waiting for ART. Studies in the USA and Europe suggest that regular use of an antifungal drug, fluconazole, may prevent cryptococcal and other fungal diseases. Similar studies have not been done in Africa but the higher incidence of cryptococcal disease in tropical settings means that there could be an even greater impact on morbidity and mortality. Generic fluconazole is now freely and cheaply available in Africa, meaning that the strategy of using fluconazole to prevent cryptococcal disease has become increasingly attractive, especially as established disease is so difficult to treat.This study has already commenced in partnership with TASO (the AIDS Support Organisation), the leading HIV care organisation in Uganda. 669 participants have been enrolled into a double blind study to compare the efficacy and safety of fluconazole with placebo, measuring cryptococcal disease and mortality. However, the incidence of cryptococcal disease has been lower than anticipated due to the extensive use of ART at the study site and screening out of participants who are most at risk. We are now seeking an extension to this study allowing enrolment of a further 870 patients thus ensuring that the study is sufficiently powerful to enable us to make firm conclusions about the benefit of this intervention.