The results of the CAPRISA trial which tested the safety and effectiveness of a 1% Tenofovir Gel Microbicide» for the prevention of HIV acquisition in women created quite a stir at the XVIII International AIDS conference in Vienna. For the first time, and after years of unsuccessful research, a randomised trial involving 889 women in South Africa showed that it was possible to prevent HIV acquisition with a gel containing an antiretroviral (ARV).

Overall the results are clear and unequivocal, after 30 months of gel use, the group of women who received the 1% Tenofovir gel showed 39% fewer HIV infections compared to the group of women who received the placebo gel (and the difference is statistically significant!).

This is a victory for the Microbicides research world that had to bear the brunt of many critics during the past years as products after products were failing to show any protective effect and in some case  were even shown to potentially increase the risk of HIV infection.

Remarkably, the Tenofovir gel showed a protective as early as 12 months after the start of the study. But because this was not a study endpoint (the endpoint was the total number of HIV infections) the trial carried on for a further 18 months.  After the first year, the product still worked but to a lesser extent. This was in part explained by a fall in the number of time the product was used (what is called “adherence”) and also by a reduction in the number of sex act.

Adherence is critical in this type of clinical trial. The only way to assess if a product works is for participating women to actually use it. The preliminary analysis of the data showed that when women used the product more than 80% of the time (and product use was quite complex, requiring a pre-sex application and a post sex application both within 12 hours before and after the sex act) then the risk of infection was 54% lower in the group using the Tenofovir gel. The risk remained lower for intermediate and low user but then the difference was no longer statistically significant. This latter result should not be over interpreted because the group were probably too small for the analysis to give a meaningful result. However, this is a point worth keeping in mind.

As noted by Salim Abdool Karim, the Chief Investigator, “task number one is better adherence”. Undeniably, adherence is a key issue that will determine the prospect of the product. “In the group that used the gel less than half of the time, the risk reduction plummeted to 28%.” Despite an intensive adherence programme and high gel acceptability (another critical factor for the success of the product), about 40% of the women in this study had below 50% gel adherence. This means that for these women, using the product would not make a difference.

There are several reasons why women would not use the gel, even if they are taking part in a trial. One is that their partner may not be aware that they are in a trial and the women are afraid of using the gel or can only use it covertly. Another reason as proposed by Salim is “fatigue”: women had to come every month to a clinic and were repeatedly told that it was not known if the gel work and that they should still use condoms (condom use was remarkably high at about 80% all along, suggesting no change in risk taking behaviour).

Nevertheless, the researchers projected that if the 1% Tenofovir gel was  used by one in three South African women at risk of infection it could contribute to saving the life of 1.3 million women over 20 years and save 820,000 life. But they admit that they are not there yet and that “the CAPRISA study is a critical first step that needs to be confirmed by other studies to enable licensure and subsequent public availability for HIV prevention”.

Such subsequent studies will have to be carefully designed to address the issues raised by the design and results of the CAPRISA Trial.

First, a much larger trial (phase III) will be required to provide more definitive and meaningful answers. As previously demonstrated with PRO 2000 (another non ARV-based unsuccessful candidate microbicide), a smaller trial may lead to encouraging results that a larger trial could nevertheless definitively quelled.

Second, the frequency of use of the product must be improved. Indeed, the worst thing that could happen to a product we know has the potential to work would be that it fails because it is not used. Male and Female condoms are sad example of such products which failed on use. Adherence would certainly be improved if the product can be used in a more flexible way. But a right balance will have to be found to ensure that flexibility is not detrimental to its effectiveness. The result of the VOICE trial, which is currently assessing daily Tenofovir gel as well as daily Tenofovir and Truvada (a combination of 2 ARVs) tablets in women in several African countries, expected in 2013 will provide useful information on how and when to use the product.

Third, though a low level of rectal intercourse was reported by the participants in this study, anal sex does happen even in Africa and it will be worth to properly and fully investigate the impact of rectal intercourse in the trial. Considering the much higher risk of infection associated to the practice and its likely contribution to the spread of the virus in the heterosexual population, a successful microbicide will have to work for the two types of sexual intercourse. It will be a vaginal and rectal microbicide.

In parallel it could be beneficial to start addressing now behaviour change associated with risk compensation and frequency of use of the product. Risk compensation can be assessed and addressed during the trial. Frequency of use can be addressed right now. Though anti-HIV microbicides does not yet exist, improving access and use of common lubricants would prepare the ground for an effective ARV-based microbicide when there will be one. Women would be prepared to switch to a different product based on previous experience with lubricants and men would be famillair with women using such products.

How the product will be marketed will be crucial to its success. Though microbicides were initially designed for women as an HIV prevention tool that they can control, it is essential, and it would be a mistake to do otherwise, to market the product broadly and not only for women. A successful product will be one that is use by women and by men (and yes men could also decide to use the product because it enhances sexual pleasure), acceptable to both women and men and enjoyed by both. Work on product branding could start now and run in parallel with managing the expectation raised by the results of the CAPRISA trial, as these must be confirmed n a larger trial before the product can be licensed for public use.

Enthusiasm, expectations, excitement are running high in the HIV prevention field and amongst those who are desperately looking and in need of an HIV prevention that not only works but that they can use easily and without the socio-cultural distress associated with other HIV prevention technologies.

Managing the next trial, the growing expectations, and the long process leading to a potential licensure are the next challenges for scientists, policy makers, politicians and the world at large. The task is monumental, but after nearly 30 years of repeated failures, a gleaming ray of hope is emerging out of an improbable product.

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