The perils of success: what if the new prevention methods work?

A debate¹ at the International AIDS Society (IAS) Conference in Cape Town in July, sponsored by the IAS and the AIDS Vaccine Advocacy Coalition (AVAC) looked at how to prepare for microbicides and pre-exposure prophylaxis (PrEP). Gus Cairns reports.

Within a couple of years’ time, we may know if two crucial new HIV prevention approaches will work. If they do, what then?

A microbicide is a substance that can be incorporated into a lubricant, gel or barrier such as a diaphragm that will stop HIV transmission during sex. And PrEP is the concept of HIV-negative people taking anti-HIV drugs in advance of sex (or needle-sharing) to prevent HIV.

Crucial trials of these new prevention methods will start announcing their results soon. In 2010, we’ll have results from the biggest microbicide trial to date, the Microbicides Development Partnership trial of PRO2000 gel.

By 2011 we’ll know about tenofovir PrEP in Thai drug users, tenofovir/FTC PrEP in South American gay men, and tenofovir gel as a microbicide in South Africa. 2012 will offer PrEP results from men and women in Africa, and from a comparison trial of tenofovir as a microbicide and PrEP.

New prevention methods in HIV have had setbacks in the last few years, but following a promising result for the microbicide PRO2000 announced earlier this year, prevention advocates are daring to believe that positive results could be on their way.  

Carl Dieffenbach, director of the AIDS Division of the US National Institute of Allergies and Infectious Diseases (NIAID) laid out an apparently straightforward development strategy. “The first thing we have to do is to prove that these concepts work. Then, with the current agents, we have to develop alternative dosing schedules to maximise adherence.  We need to engage our partners in social marketing programmes that are also pieces of operational research. How are we going to market these products?”

“We also need to keep working on new agents,” he said, echoed by Yasmin Halima, the new director of the Global Campaign for Microbicides: I am really worried about the lack of a drug pipeline for PrEP. If tenofovir doesn’t work, we’re stuffed.”

Others responded that the original question of ‘proof of concept’ was not a simple one. What level of efficacy would be regarded as a success? The PRO2000 trial was powered to demonstrate a protective effect of only 30%: Most panel members said that if the second trial demonstrated this, it would not be enough efficacy to take the product forward.

What would be enough? Most audience members said they would be happy with efficacy of 40 to 60% (roughly comparable to male circumcision), but some would want the product to stop at least four out of five infections (80% efficacy, comparable with real-world condom use).

Sharon Hillier, Director of the Microbicides Trials Network, defined this as the problem of the ‘partial yes’. She foresaw that people would need to use a variety of different prevention methods, rather than putting all their faith in one.

“We need to identify approaches that are going to be used by a wide variety of people,” she said, “which they are going to want to use and have available. We need funders willing to buy them and regulators willing to register them. We need to make sure our successes are not just clinical.”

Stephen Becker of the Bill and Melinda Gates Foundation, a prime private-sector sponsor of new prevention technologies said: “We can’t wait until clinical proof of concept has occurred,” he said. We need to investigate delivery channels, how we engage with policy makers, and how we will market these approaches now.”

Catherine Hankins contrasted PrEP with microbicides. Although complementary, they may have to be prescribed and marketed in very different ways.

Prophylaxis pills would always have to be prescribed and countries would need to consider strategies for PrEP availability.

“We will need to strengthen the knowledge of countries as to where their next thousand HIV cases are going to come from. Which groups do I give it to and in what way?

HIV drug side-effects might make PrEP unpopular: “If you are going to introduce it in a country with widespread experience of lipodystrophy due to d4T, you will find widespread resistance to it.”

In contrast, some delegates said that if PrEP trials came up with a positive result a black-market culture might follow. Morenike Ukpong of Nigeria’s New HIV Vaccine and Microbicide Advocacy Society said: “I tell you, if a result is announced at a conference, PrEP will be on the market in 24 hours.”

Professor Helen Rees, Executive Director of South Africa’s Reproductive Health and HIV Research Unit (RHRU), agreed: “If PrEP works, we can’t waste a lot of time debating registration, because people will vote with their feet and start to use it. There are several studies in Africa to show that people are secretly taking it already.”

She emphasised the need to find out if PrEP was safe for groups excluded from the trials such as pregnant women and adolescents, and, like many delegates, stressed the urgent need to do trials of intermittent use.

With microbicides, unlike PrEP, the potential still exists that they could eventually be sold over the counter.

Acceptability studies showed that people liked microbicides. Sharon Hillier commented: “If they’re going to make sex fun, people who don’t consider themselves at risk and who wouldn’t take a medicine might use a microbicide.”

In one trial in Uganda, she said, the microbicide had an unexpected double effect: firstly, women said it made sex fun and then, because of that, their male partners were more faithful. But Dr Francois Venter, Director of the RHRU, described himself as a microbicide sceptic. It was going to be an extremely hard job persuading funders to pay for approaches with only partial efficacy, he said.  “It’s not just about whether these interventions will work and can be promoted ethically,” he said. “Can health systems afford them?

Dr Yogan Pillay, Director of Strategic Health at South Africa’s Health Ministry, agreed, commenting that it was challenging enough “pay[ing] for the cost of HIV treatment today and paying for TB and opportunistic infections too.”

Pillay and others drew parallels between the new technologies and circumcision. Three conclusive randomised, controlled trials showing that circumcision prevented about 60% of infections in men had not translated into national programmes.

Patrick Ndase, regional physician for the Ugandan PrEP trial, said “We need to do convincing modelling studies of efficacy and cost-effectiveness so that these options become really attractive to people who are already trying to fund HIV or TB treatment. And we need to decide what language we use with the ministries and the funders that is going to make them decide to support an approach with 50% efficacy.“

Zeda Rosenberg, Director of the International Partnership for Microbicides, summed up the feeling of the meeting. “We’re used to scepticism,” she said. “The sceptics used to say ‘it won’t work and women won’t use it’. Now they say ‘You won’t be able to fund and deliver it to the people who need it’. That’s progress!”