A vaginal gel containing the microbicide PRO2000 failed to prevent HIV transmission, according to results from a randomized, controlled trial that enrolled more than 9,000 African women who inserted either PRO2000 or a placebo gel before having sex. The results were published Sept. 20 by the Lancet.

But the phase III trial’s lead investigator said that some of the lessons learned during the trial bode well for anti-HIV gels at a time when more effective ones are being tested, and that the failure of one agent shouldn’t be confused with the failure of gels as a prevention strategy – not least because women like using them. (Lancet 2010 Sept. 20 [doi:10.1016/S0140-6736(10)61086-0]).

For their research, Sheena McCormack of the U.K. Medical Research Council’s Clinical Trials Unit, in London, and colleagues, randomized 9,385 women aged 18-45 years (16 years and older in two countries) from 13 clinics in Tanzania, Zambia, Uganda, and South Africa to receive prefilled vaginal applicators with gel containing PRO2000 2%, PRO2000 0.5%, or placebo (ratio, 1:1:1). Professional sex workers (or women who are likely to have sex more than 14 times a week) and pregnant women were not enrolled. All women were HIV negative at enrollment; all were instructed to insert the gel before sexual intercourse.

The results showed that although compliance with the gel regimen was nearly 90% (measured in part by the return of used applicators), neither concentration of PRO2000 was more effective than was placebo in preventing new HIV infections after a year of use.

PRO2000, a synthetic naphthalene sulphonate polymer, had been shown to prevent HIV transmission in primate trials, and data from a smaller and unrelated study (presented in Montreal at a 2009 conference on retroviruses and opportunistic infections) had shown a 30% reduction in infections with the 0.5% concentration of PRO2000, compared with placebo, a statistically insignificant but promising result.

Dr. McCormack and colleagues’ interim trial results had shown that 2% PRO2000, the higher of the two concentrations tested, was ineffective as early as 2008, when the 2% arm of the trial was discontinued. However, the investigators had hypothesized that the higher-concentration gel might prove to be the less effective because of its potential to irritate the vagina, undermining some of its potential protective effect.

At the study’s end, the less-concentrated gel also disappointed, with the incidence of new HIV infections per 100 woman-years at 4.5 for 0.5% PRO2000 and 4.3 for placebo. Although it had biological potency in the lab, “it seemed that the most likely explanation is that the ejaculate disturbs the equilibrium in some way,” precluding PRO2000’s effectiveness, Dr. McCormack said in an interview.

But even though the final results were a surprise and a letdown, Dr. McCormack said, much was learned during the trial that could prove to be good omens for a gel containing the antiretroviral drug tenofovir. In interim results from an ongoing South African trial (n = 889) released in July (Science 2010 July 19 [doi:10.1126/science.1193748]), tenofovir 1% vaginal gel, used before sex, was shown to reduce a woman’s risk of HIV infection by 39%. Women who used the gel 80% of the time saw a 54% reduction in HIV infections.

Dr. McCormack’s group saw more than 80% compliance in the PRO2000 study, and found that – despite reports of some mild adverse effects, such as itching, in both the treatment and placebo arms – women generally reported that they enjoyed using the gel, “and a portion raved about it,” Dr. McCormack said. “Adherence around the sex act has been very good,” comparing favorably with condom use, which was found to be very low among enrollees in some of the trial countries.

The popularity of the gels would seem auspicious for an effective one, but Dr. McCormack, who is struggling to raise funds for a new study involving tenofovir gel, said she feared a waning of donor interest in vaginal gels – many of which have been disappointments – at the time when a truly effective antitransmission agent seems to have finally been discovered. This month, the New York Times reported that the U.K. government, which funded much of Dr. McCormack’s study and contributed to other gel trials, had become noncommittal on its plans to fund further research into gels.

“I am anxious not to confuse the results of our trial with [the tenofovir trial]. PRO2000 is much less potent than tenofovir,” Dr. McCormack said. “You’ve got to think about this in a bigger picture: At the moment, there’s a real possibility in tenofovir gel.”

Dr. McCormack’s study was funded by the U.K. government, the European and Developing Countries Clinical Trials Partnership, the International Partnership for Microbicides, and Endo Pharmaceuticals, the manufacturer of PRO2000, which donated the gels for the study. One coauthor of the study was an employee of Endo Pharmaceuticals with an equity interest in the company.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

根据一项随机对照研究结果，应用含有抗微生物药剂PRO2000的阴道凝胶剂并不能预防HIV传播（参见2010年9月20日出版的Lancet， [doi:10.1016/S0140-6736(10)61086-0]）。但该三期临床研究的主要研究人员认为，该研究依然为正在进行中的更有效的抗HIV凝胶临床试验提供了一些有用的信息。至少应用药物凝胶作为预防HIV传播的策略，受到妇女的欢迎。

 

该研究由来自伦敦英国医学研究理事会临床实验研究所的Sheena McCormack博士及其同事完成的。研究涉及9385名妇女，年龄在18至45岁，来自坦桑尼亚、赞比亚、乌干达和南非的13个医疗中心。她们使用预装药物的阴道涂药器，被随机分为3组，即含2％PRO2000凝胶组、含0.5％PRO2000凝胶组以及安慰剂组，各组人数相同。性工作者（或每周性交次数可能超过14次者）以及孕妇不纳入研究。所有女性入组前HIV检测为阴性，在性交前阴道应用凝胶。

 

结果显示，经过1年的使用，虽然参试者对凝胶的使用依从性高达近90%，但无论何种浓度的PRO2000与安慰剂相比，均未表现出预防HIV感染的功效。每100名妇女每年新感染HIV的数量在0.5%PRO2000凝胶组和安慰剂组分别为4.5人和4.3人。

 

PRO2000是一种合成的聚合萘磺酸盐，在实验室和小规模的临床研究中显示，0.5%PRO2000与安慰剂相比，可减少30%HIV感染风险。

 

虽然该研究结果令人失望，但研究者认为该研究能为含有抗逆转录病毒药物替诺福韦的凝胶研究提供有用的信息。上述研究正在南非进行，其中期成果已发表在2010年7月19日出版的《科学》杂志上（[doi:10.1126/science.1193748]）。

 

研究者认为，PRO2000研究至少证明参试者使用凝胶的依从性好，妇女喜欢使用凝胶。他们希望此项研究结果不要让有关方面减少对使用凝胶预防HIV感染方面研究的资金投入。

 

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