February 9, 2009
There's nothing like hearing the results of studies directly from those who actually conducted the research. In this interview, you'll meet one of these impressive HIV researchers and read his explanation of a study he presented at CROI 2009.
My name is Gerardo Garcia-Lerma. I work in the Division of HIV/AIDS Prevention at the U.S. Centers for Disease Control and Prevention. I'm pleased to discuss the research that we are doing on the efficacy of intermittent, oral, pre-exposure prophylaxis [PrEP] using a macaque model.
More than 30 million people are infected with HIV-1, and there are around two and a half million new infections every year. It is evident that we need to identify new HIV prevention interventions that can complement the interventions that we have now. The use of antiretroviral drugs as oral pre-exposure prophylaxis has been gaining considerable attention in the past few years: Because we don't have a vaccine, we are looking for new and additional medical interventions.
Gerardo Garcia-Lerma, Ph.D.
In this study, we wanted to investigate whether intermittent PrEP -- one dose of antiretrovirals prior to exposure and a second dose after exposure -- could be effective.1
Essentially, we saw that this intervention actually protects the animals against rectal transmission. We had a repeat-exposure model of transmission in macaques: In the model, we exposed the animals to the virus once every week for a total of 14 weeks. We saw that regardless of when we gave the drugs to the animals, we could reduce the risk of infection compared to untreated animals. For instance, we have groups of animals that we gave one dose of Truvada [tenofovir/emtricitabine, TDF/FTC] either one day or three days prior to exposure, followed by a second dose two hours after exposure. These animals had a reduced risk of infection of around 15-fold, which was statistically significant compared to the control animals.
In essence, these findings in macaques provide the rationale for possible future generation PrEP trials that can address whether intermittent PrEP modalities might be as effective as daily PrEP modalities. Within that, these animal models give us the opportunity to assess several concepts and prepare for next-generation PrEP trials in humans.
How is this trial different than the previous trials that were done?
The previous trials that we did in animals were on daily pre-exposure prophylaxis. This trial is what we call an intermittent trial, which uses a very limited number of drug doses. In our case, it's limited to two doses: one dose of drug prior to exposure, and a second dose of drug after exposure.
What was the dose?
We've done some studies to look for the dose that is equivalent to the dose of drugs that is used in humans. We used in the monkeys an equivalent dose to that used in humans.
This is given orally?
This is given orally to the animals.
Do we know yet what kind of intermittent schedule would be ideal?
We don't know. The power that we have with animal studies is that we can evaluate different intermittent modalities. For instance, we can evaluate modalities that basically are exposure-driven; you give the drug to the animals around the time of exposure. Or we can evaluate modalities that are not exposure-driven -- for instance, what we call a stand-in dose, which is one or two doses of Truvada in a week, followed by a second dose after exposure. That's what we call independent of the time of exposure.
We can evaluate all these modalities. Actually, the animal data that we have presented at this conference suggest that modalities that are independent of the time of exposure appear to be more protective than if the doses are given right around the time of exposure.
Were there any adverse effects?
No. These are drugs that have been proven in animals before. At the doses that we used, there hasn't been any adverse effect.
Is there any risk of drug resistance?
We monitor closely the animals that fail using sensitive tools. We haven't noted any resistance in any of the failures that we have seen. But that's something that we definitely monitor very carefully.
What are the next steps?
We are continuing and expanding these studies. There are several modalities we want to evaluate -- for instance, whether one single drug dose could prevent infection or offer some protection. This study is a rectal transmission model, so we are also planning on evaluating the same set of studies in a vaginal transmission model to see whether we can also protect macaques against vaginal transmission with oral drugs.
This was a single drug?
This is Truvada.
You didn't compare it with tenofovir [TDF, Viread] alone?
No, we didn't. That comparison was done in the study on the daily administration of PrEP, which showed that two drugs work better than a single drug; so we decided to do the intermittent studies with two drugs, because they were more effective in daily administration.
At what point will we be doing this in humans?
Right now there are several clinical trials on daily PrEP in humans. We expect to have some results from those at the end of this year or next year. The results from those trials are going to be very informative because they will let us know: first, efficacy; and second, what the relationship is between drug pharmacokinetics, drug levels and protection. We need to get information from the daily PrEP trials before we can [proceed with our intermittent trials].
Where are those trials taking place now?
They are taking place all over the world. There are seven clinical trials in different countries and continents: Africa, Asia, South America. There are some studies in the U.S. also.
They all involve oral dosing?
Yes, either with tenofovir or with Truvada. They are all daily PrEP.
Oral PrEP is not characterized as a microbicide?
No, this is oral pre-exposure prophylaxis. Microbicides are now referred to as "topical." Topical PrEP, if you want. This is oral PrEP.
Thank you very much.
This transcript has been lightly edited for clarity.