With no AIDS vaccine in sight, what's next?

With a number of HIV vaccine trials ending in disappointment, public health officials and scientists are seeking new ways to maximize the application of already proven prevention strategies. They also are examining the preventive potential of medications more often used to treat those already infected.

"We know antiretrovirals can prevent mother-to-child transmission and transmission to health care workers," said Lynn Paxton, MD, MPH, leader of the antiretroviral prophylaxis and microbicides team at the Centers for Disease Control and Prevention's Division of HIV/AIDS. "It's a reasonable idea to expand its use for other forms of HIV transmission."

At least seven trials, including three run by the CDC, are investigating pre-exposure prophylaxis, or PrEP. The goal is to determine if tenofovir, with or without emtricitabine, can prevent contracting infection through sex or injection drug use.

This area of research offers promise because, although an effective vaccine is not imminent, antiretrovirals have improved significantly. For example, once-daily dosing is possible. In addition, the side-effect profiles tilt the risk-benefit profile in antiretrovirals' favor.

It is part of what was called "combination prevention" at the recent XVII International AIDS Conference in Mexico City. It also is a nod to the success of "combination treatment," which was the catchphrase more than a decade ago. This updated iteration of that concept involves taking advantage of several preventive strategies at once -- ranging from PrEP and policy changes to increasing the availability of condoms and encouraging circumcision.

"We cannot be sure if and when a tool to eradicate HIV is going to become realistic. You can despair, or you can look at what is available that's working," said Dr. Julio Montaner, president of the International AIDS Society. "We can combine multiple strategies we know that work."

Part of this school of thought also includes providing greater access to care for those who already have the virus, because data indicate that lower viral loads make transmission less likely. The results of a mathematical model by Dr. Montaner, reported in the July Journal of Infectious Diseases, suggested that increasing the proportion of infected people getting treatment from 50% to 75% could cut new infections by 30% over the next 25 years. Increasing the treatment to 90% of people carrying the virus would cut new infections by half.

Those working on the issue say increased HIV testing is critical. The American Medical Association endorses routine testing in the medical setting. Data also suggest that more people are becoming aware of their status. A study in the Oct. 3 Morbidity and Mortality Weekly Report documented a drop in the number of people who are infected but don't know it, from 25% in 2003 to 21% in 2006.

"We have to use the tools we have available, test individuals and get them into care," said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases.

Focusing on the basics

Work toward a vaccine, however, is far from over. Rather, more emphasis is being placed on understanding the basics of the virus and how the immune system confronts it.

"We tried the things that we needed to try because they were obvious, and, if they had worked, wouldn't that have been great," said Kathleen Collins, MD, PhD, an associate professor of internal medicine, microbiology and immunology at the University of Michigan, Ann Arbor. She researches how HIV evades the immune system. "We need to go back and understand why this virus is so unique."

To encourage more basic science, NIAID announced in June the creation of a Vaccine Discovery Branch within its Vaccine Research Program in the Division of AIDS. The next month, the Institute announced that its vaccine research agenda would fund more preclinical studies.

HIV vaccine "is the challenge for this generation of scientists," Dr. Dieffenbach said.

These actions were taken in response to a growing acknowledgment that, despite considerable investment, a successful vaccine most likely will not be produced using current knowledge. For instance, last year the STEP trial, a phase II vaccine study run by Merck & Co. Inc. and NIAID, became the latest HIV vaccine study to be discontinued for a lack of effectiveness. In its wake, several others were trimmed or put on hold. Experts now hope this shift of scientific focus will increase the chances that the next round of potential vaccines that advances to the clinical trial stage will produce the desired results.

"We do not know so much about the mechanisms of HIV tissue pathogenesis," said Leonid Margolis, PhD, chief of the section of intercellular interactions at the National Institute of Child Health and Human Development. "There is always a chance that the next vaccine or microbicide will work, even if we do not understand these mechanisms, but the probability is low."

Work also continues on understanding why some infected people don't get sick. A paper in the August Journal of Virology demonstrated that elite suppressors most likely have something different about their immune systems rather than a defective virus. The authors suggest better understanding of this phenomenon could lead to an effective vaccine.