Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial.
Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial.
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DOI：
10.1371/journal.pctr.0020027
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发表时间：
2007-05-25
期刊：
影响因子：
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通讯作者：
Cates W
中科院分区：
文献类型：
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作者：
Peterson L;Taylor D;Roddy R;Belai G;Phillips P;Nanda K;Grant R;Clarke EE;Doh AS;Ridzon R;Jaffe HS;Cates W
该试验的目的是调查每日剂量 300 毫克的富马酸替诺福韦二吡呋酯 (TDF) 与安慰剂相比，在预防女性 HIV 感染方面的安全性和初步有效性。这是一项 2 期、随机、双盲、安慰剂对照试验。该研究于2004年6月至2006年3月在加纳特马进行；喀麦隆杜阿拉；和尼日利亚伊巴丹。我们招募了 936 名艾滋病毒感染高风险的艾滋病毒阴性女性参加这项研究。参与者按照 1:1 的比例随机分组，每天服用一次 300 毫克 TDF 或安慰剂。主要安全终点是肾功能的2级或更高血清肌酐升高（>2.0mg/dl），肝功能的3级或4级天冬氨酸转氨酶或丙氨酸转氨酶升高（>170U/l），以及3级或4级磷异常（<1.5mg/dl）。有效性终点是感染 HIV-1 或 HIV-2。研究参与者为初步安全分析贡献了 428 人年的实验室测试。治疗组之间的临床或实验室安全结果没有出现显着差异。研究参与者为主要有效性分析贡献了 476 人年的 HIV 检测，在此期间发生了 8 次血清转化。在随机接受 TDF 的参与者中诊断出 2 例（每 100 人年 0.86 例），在接受安慰剂的参与者中诊断出 6 例（每 100 人年 2.48 例），比率为 0.35（95% 置信区间 = 0.03-1.93），未达到统计显着性。由于喀麦隆和尼日利亚研究地点过早关闭，计划中的人年随访和研究力量无法实现。未感染 HIV 的女性每日口服 TDF 与临床或实验室不良事件的增加无关。由于研究期间观察到的艾滋病毒感染人数很少，因此无法最终评估有效性。 背景：世界卫生组织估计，2006 年约有 430 万人新感染艾滋病毒。一些国家的感染率似乎正在上升，迫切需要找到安全有效的方法来防止艾滋病毒从一个人传播到另一个人。许多预防成人之间艾滋病毒传播的策略，例如使用安全套或改变行为，并不完全可靠，尤其是妇女，可能并不总是能够协商使用安全套。需要采取其他策略来降低艾滋病毒传播的风险。其中一种策略称为“暴露前预防”。该策略涉及感染艾滋病毒高风险的个人服用抗病毒药物来预防艾滋病毒感染。一种特殊的药物，富马酸替诺福韦二吡呋酯，目前被批准用于治疗艾滋病毒感染，并且也作为暴露前预防的有力候选药物进行研究。该研究在此报告了在加纳、喀麦隆和尼日利亚三个不同地点进行的试验结果。在该试验中，936 名未感染 HIV 但感染风险较高的女性被随机分配每日服用替诺福韦片剂或安慰剂片剂。研究人员计划对这些女性进行为期 12 个月的随访，主要疗效分析将集中于比较试验两组之间的新 HIV 感染率。主要安全性分析包括对血液样本进行的特定实验室测试，这些测试可能表明肝或肾功能异常。在整个试验过程中还收集了安全数据，并将出现的健康问题分类为不良事件或严重不良事件。 该试验表明：不幸的是，该试验并未按计划完成。两个地点（尼日利亚和喀麦隆）在招募计划参与者人数之前或在所有参与者完成全面随访之前关闭。因此，该试验没有足够的数据来确定替诺福韦是否可以降低艾滋病毒感染的风险。只有两个站点为主要安全性分析提供了数据，该分析着眼于肝肾功能。研究人员没有发现服用替诺福韦的参与者和服用安慰剂的参与者在这些安全性终点上存在任何统计学上的显着差异。治疗组之间的不良事件数量也没有统计学上的显着差异。主要疗效分析发现，替诺福韦组有 2 例新感染 HIV 病例，安慰剂组有 6 例新感染 HIV 病例。由于本研究期间仅观察到八个有效性终点，因此这些组之间的艾滋病毒发病率差异不具有统计学意义。 优点和局限性：该试验的优点是它的设计正确，以实现研究的最初目标，包括适当隐藏随机化以及对参与者和研究人员对治疗分配采取盲法。这项研究的主要限制是关闭了两个研究中心，这意味着该研究没有足够的能力来评估主要疗效分析中试验组之间的差异。 证据贡献：在本试验完成时，没有来自评估抗逆转录病毒药物预防艾滋病毒感染的随机研究的其他证据。然而，这项试验无法明确说明替诺福韦是否可以降低高危女性感染艾滋病毒的风险。为了回答这个问题，正在进行和未来的试验至关重要。这里报道的试验提供了关于未感染艾滋病毒的高危女性每日服用替诺福韦的安全性的重要数据；安全性数据令人鼓舞，表明与安慰剂相比，替诺福韦的使用与不良事件的增加无关。
The objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women. This was a phase 2, randomized, double-blind, placebo-controlled trial. The study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria. We enrolled 936 HIV-negative women at high risk of HIV infection into this study. Participants were randomized 1:1 to once daily use of 300 mg of TDF or placebo. The primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2. Study participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03–1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved. Daily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study. Background: The World Health Organization has estimated that in 2006 around 4.3 million people were newly infected with HIV. Infection rates seem to be increasing in some countries, and there is an urgent need to find safe and effective ways of preventing HIV from being transmitted from one person to another. Many strategies for the prevention of HIV transmission between adults, such as use of condoms or changes to behavior, are not completely reliable, and women, in particular, may not always be able to negotiate condom use. Additional strategies for reducing the risk of HIV transmission are needed. One of these strategies is called “pre-exposure prophylaxis.” This strategy involves individuals who are at high risk of becoming infected with HIV taking antiviral drugs to prevent HIV infection. One particular drug, tenofovir disoproxil fumarate, is currently approved as a treatment for HIV infection, and is also being investigated as a strong candidate for pre-exposure prophylaxis. The research presented here reports on results of a trial carried out at three different sites in Ghana, Cameroon, and Nigeria. In the trial, 936 women who were not infected with HIV but who were at high risk of becoming infected, were randomized to take tenofovir tablets daily or, alternatively, placebo tablets. The researchers planned to follow up with the women for 12 months, and the primary analysis for efficacy would focus on a comparison of the rate of new HIV infections between the two arms of the trial. Primary safety analyses included specific laboratory tests carried out on blood samples that might point to abnormalities in liver or kidney function. Safety data were also collected throughout the trial, and health problems that arose were classified as adverse events or serious adverse events. What this trial shows: Unfortunately, this trial was not completed as planned. Two sites (Nigeria and Cameroon) were closed either before the planned number of participants had been recruited or before all participants had completed full follow-up. Therefore, not enough data were available from this trial to determine whether tenofovir reduced the risk of HIV infection. Only two sites contributed data for the primary safety analyses, which looked at liver and kidney function. The researchers did not see any statistically significant differences in these safety endpoints between participants taking tenofovir and those taking placebo. There were also no statistically significant differences between the treatment groups in the number of adverse events. The main efficacy analysis found two new HIV infections in the tenofovir group and six in the placebo group. Because only eight effectiveness endpoints were observed during this study, the difference in HIV incidence between these groups was not statistically significant. Strengths and limitations: A strength of this trial is that it was correctly designed to address the original objectives of the study, involving appropriate concealment of randomization and blinding of participants and study staff to treatment assignment. The main limitation of this study was the closure of two study sites, which meant that the study did not have sufficient power to assess differences between trial arms in the primary efficacy analysis. Contribution to the evidence: At the time this trial was completed, there was no other evidence from randomized studies that evaluated antiretroviral drugs for prevention of HIV infection. This trial cannot, however, definitively address whether tenofovir reduces the risk of HIV infection among at-risk women or not. Ongoing and future trials are essential in order to answer this question. The trial reported here provides important data on the safety of daily tenofovir among high-risk HIV-uninfected women; the safety data are encouraging and suggest that tenofovir use is not associated with increased adverse events as compared to placebo.