Gilead Sciences announced last May that the National Institutes of Health has embarked on a phase I study to determine the safety and acceptability of tenofovir gel to block vaginal transmission of HIV. Tenofovir's potential goes beyond such microbicide use to true pre-exposure prophylaxis (PREP).
In October, the Bill & Melinda Gates Foundation agreed to fund a groundbreaking trial on using standard oral tenofovir as an HIV preventive. Family Health International (FHI) of Research Triangle, NC will oversee this study. By the end of this year, FHI will begin enrolling some 1,600 women from developing countries who are at high risk for sexually acquiring HIV.
Using anti-HIV drugs as prophylaxis is not a new concept, especially in populations where condom use is unreliable. Women employed as sex workers in many African countries have difficulty negotiating condom use with their partners. These women could greatly benefit from a prevention method that they can control. And with effective vaccines remaining unavailable in the near future, new attention has being given to using approved drugs to prevent HIV in adults. "This is a really hot topic and one that looked encouraging," said Dr. Ward Cates, President of FHI's Institute for Family Health.
Tenofovir is also preferred to nevirapine because HIV very rapidly develops resistance to the latter drug. In contrast, resistance to tenofovir develops relatively slowly. In lab tests, the HIV strains that are resistant to tenofovir tend to be less virulent than nonmutated virus.
Resistance is an important threat in situations where large numbers of people are taking the medication sporadically based on their sexual activities. Intermittent exposure to a drug helps a virus like HIV develop resistance to that drug.
FHI's PREP study will mainly evaluate primary safety data, including liver, kidney, and bone function. Bone mineral density will be subject to close monitoring because it is the only area where safety issues have arisen with tenofovir. In certain studies, animals receiving tenofovir developed a bone disorder called osteomalacia (calcium depletion). The dose in these studies was much higher than that prescribed for humans, and the condition was treated and reversed completely when drug use was discontinued.
Studies that tested tenofovir's ability to prevent infection in monkeys, both before and after exposure, have been very encouraging. Cates predicts that tenofovir will have a major impact on prevention in resource-poor countries, where women are often employed as transient sex workers.
Female volunteers assigned randomly to the experimental arm of the study will receive a 300 mg tenofovir pill once daily. Those in the control arm will receive a placebo pill, and both active and placebo arms will receive counseling on safe sex and condom use. The study is blinded and will last for one year.
No prior acceptability studies have been done to ascertain if healthy volunteers are willing to take a pill every day or to clarify how tenofovir PREP affects their sexual behavior. These issues will be analyzed during the course of the study, but the main goal is to obtain information on the safety and tolerability of tenofovir in an uninfected population. FHI is hoping to show that the drug is acceptable, safe, and easily administered.
The organization is enrolling an unusually large cohort for an initial study. It hopes that if the extent to which tenofovir protects against HIV will also come out of the study. "Ultimately, the drug could be so effective that we'd be able to show that tenofovir protected versus placebo in this study," said Cates.
If tenofovir is deemed effective, Gilead will consider providing the drug in those geographic areas where need for prevention is greatest. "There's a good chance that tenofovir could have an effect in this setting," said Jim Rooney, Gilead Sciences' Vice President of Clinical Research. "We would be committed to making the drug available in those areas." Gilead last winter announced plans to provide tenofovir for HIV treatment at "no profit" to established clinics in 68 poor countries.
"In absence of a vaccine, it makes sense to look at other strategies to prevent infection. We're very excited about this," said Rooney. But he added: "First we want to answer, does it work?"