Microbicides - from results to reality

The results are exciting - a vaginal gel containing the antiretroviral (ARV) drug, tenofovir, has shown a 39 percent reduction in HIV risk. But the reality is that it could take several years before a product is on the market that women can use.

The dust has barely settled after the announcement of the first positive results from a microbicide trial, but scientists and policy makers are already asking themselves, 'What's next?'

Funded by the US and South African governments, the Centre for the AIDS Programme of Research in South Africa (CAPRISA) trial involved 889 HIV-negative, sexually active South African women who were considered to be at high risk of HIV infection. Half of the women were given vaginal applicators containing a 1 percent concentration of tenofovir gel, while the other half were given a placebo gel. The women were asked to insert a dose of the gel 12 hours before sexual intercourse and a second dose within 12 hours after intercourse.

Over the course of the year-long study, 98 women became HIV positive - 38 in the tenofovir gel group compared to 60 in the placebo gel group. On average, adherence to the gel was over 70 percent, but among women who used the tenofovir gel for more than 80 percent of sex acts the gel provided greater protection from HIV.

"We believe that the most responsible plan of action now is to quickly and efficiently articulate the sequence of steps necessary for confirmation and follow-up of these results, while also aggressively planning for potential roll-out of a licensable product," Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition, said in a statement.

"As exciting as this result is - and as important as it is to follow it up without delay - the reality is that this product will not be available for widespread introduction tomorrow," Mitchell cautioned. "It is critical to manage expectations while maintaining urgency."

"It's very early, we still need to analyze all the data - and the study collected a lot of very good data - and understand it better before we get to the point of developing a product," Mitchell Warren, head of the AIDS Vaccine Advocacy Coalition (AVAC), said at the International AIDS Conference in Vienna.

For a start, there are questions about whether a 39 percent reduction in risk is enough to warrant developing a product. "It's not ideal, but in women who adhered to the gel, we saw a 54 percent risk reduction - comparable to the protection afforded by male circumcision, which is widely accepted as an HIV prevention method," said Quarraisha Abdool Karim, co-principal investigator of the study.

"More importantly, for women who have little or no choice in whether and when they have sex, it is going from zero to 39 or 54 percent - it's better than nothing," said Karim, who is also associate director of the Centre for the AIDS Programme of Research in South Africa (CAPRISA), which conducted the trial.

Investigators also noted that the gel reduced the risk of women contracting herpes simplex virus-2 (HSV-2) by 51 percent, a significant finding in HIV prevention, because women who are positive for HSV-2 are twice as likely to contract HIV as those who are HSV-2 negative.

"It's an important first step, but we now need to move it into other people's hands and work with the regulatory bodies to understand what needs to happen before it gets approval," Karim said. "It would be quite unethical if, four or five years from now, we are still saying, 'Yes, we know it works, but we haven't put it in the hands of the women who need it'."

In South Africa, the Medicines Control Council will play a critical role in deciding what further research needs to be done before a product can be approved and put on the market.

Cost

Cost is also an issue. A new report by the HIV Vaccines and Microbicides Resource Tracking Working Group found a slight decline in microbicide funding between 2008 and 2009 and warned that further success in the field of prevention research depended on the continued goodwill of donors.

The tenofovir gel produced for the trial, which was funded by the governments of the United States and South Africa, was made by the pharmaceutical giant, Gilead, and cost US$0.50 for each two-dose application, but it is hoped that larger-scale manufacturing would bring the price down significantly.

The good news is that Gilead has given a royalty-free license to the International Partnership for Microbicides and the research group, CONRAD, to develop, manufacture and arrange for distribution of the product in low-income countries.

"We are not sure in what form the product will eventually come," said Henry Gabelnick, CONRAD executive director. "The applicator might be reusable [applicators were only used once in the study], it might come in toothpaste type tubes ... we don't know."

Product development

Karim noted that dispensing methods, dosages and situational needs would have to be investigated. "Some have suggested that it could be used as post-exposure prophylaxis after rape ... there is potential for foams, pills or vaginal rings. We would like to offer women a menu of options ... [and] hear from them what product they feel most comfortable with," she told IRIN/PlusNews.

The ongoing Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial will enrol 5,000 sexually active HIV-negative women at sites in Zimbabwe, Uganda, South Africa and Malawi.

VOICE is expected to produce results in 2013, and will be important in confirming the CAPRISA findings and comparing a variety of forms for a prospective product. The trial is testing daily use of a gel containing tenofovir, as well as daily use of two different ARV tablets, tenofovir and truvada.

Various other prevention products, including pre-exposure prophylaxis (the use of ARVs to prevent HIV in high-risk groups) are also being researched.

"One of the best things about the CAPRISA trial is that it gives us time to find out what the regulatory authorities will require if VOICE is successful, and to prepare for rollout ... these products should not sit on the shelf for years, undeveloped," AVAC's Warren said.

Implementation

Policy development could delay rollout. After three successful randomized controlled trials in 2006 showed that male circumcision could reduce HIV risk, the World Health Organization (WHO) and UNAIDS developed policy guidelines for national programmes, but nearly four years on, few countries have provided large-scale male circumcision and some do not even have national policy guidelines.

Distributing the product could be particularly difficult in Africa, where sexual and reproductive health services are poorly delivered and under-utilized. WHO noted that contraceptive use in sub-Saharan Africa remained at just 20 percent.

"We would need to see a lot of community mobilization around the product before it becomes available," said Vuyiseka Dubula, general secretary of the South African lobby group, Treatment Action Campaign (TAC).

"We would need to make the product sexier, more attractive to women, and to ensure that there is a lot of public health messaging and social marketing around it," said Samukeliso Dube of the Global Campaign for Microbicides. "And then we would need to make the product available to every woman who needs it." - PlusNews

 

August 2010