BETHESDA, MD—There are at least 33 million people infected with HIV living in the world today. In the U.S. there are a million infected people, and at least 60,000 new cases a year. And if scientists do not find ways to slow and stop the spread of transmission there might be as many as 100 million HIV-infected people in the world by 2020, according to Myron Cohen, M.D., director of the National Institutes of Health Sexually Transmitted Diseases clinical trials unit and a core director of the NIH CHAVI (Center for HIV/AIDS Vaccine Immunology). Dr. Cohen, professor of public medicine at the University of North Carolina, came to the NIH campus last month to speak to the next generation of HIV researchers about what areas they will need to target if the epidemic is to be stopped.

“Where is HIV going next?” Dr. Cohen asked. “For one thing, it’s going to stay in Africa. This problem is going to go on for at least a generation. HIV is not going to leave Africa in my lifetime, and probably not the student’s lifetime.” Sub-Saharan Africa accounts for approximately two-thirds of HIV-infected individuals in the world.

“India also has a big epidemic, but the surveillance is poor, so we don’t know how bad it is. China has a big epidemic, but again the surveillance is poor—at least a million cases, probably as many as two million,” Dr. Cohen said. “China announced recently, much to my surprise, that the number one death from infectious diseases in China is death from HIV. To admit that HIV deaths are number one in a country where HIV treatment is free is a pretty potent acknowledgement.”

Targeting Transmission

When it comes to talking about an epidemic, much of the discussion revolves around numbers, and there is one set of numbers that determines whether an epidemic will continue spreading, an equation calculating the epidemic spread of the disease: Ro=bDC. Beta is the efficiency of transmission, D is duration of infectiousness, and C is the number of people exposed. If Ro is greater than 1, than the epidemic is sustained. “These are the numbers we have to worry about,” Dr. Cohen said. “We’re trying to get Ro less than 1 to try and implode the epidemic.”

“For most infectious diseases, D is pretty short,” he explained. “They have a window of infectious. They transmit or they don’t transmit, and then it’s gone. But in HIV, the duration of the disease is very long, helping to drive the epidemic.”

The best chance for physicians to impact the spread of the disease is to focus on beta, on how infectious the disease is, how susceptible people are to it, and the probability of a transmission event. The infectiousness of HIV is not homogenous, but heterogeneous over time and conditions. Many things affect the infectiousness of an infected individual: the stage of the disease, coinfections, genital tract changes and genetic factors. Similarly, there are things that affect susceptibility, including STDs, bacterial vaginosis, circumcision and genetic factors.

All of these factors are focus points for researchers looking to stop the spread of the disease by making it harder to transmit, Dr. Cohen said. They also highlight the biggest problems in understanding transmission. Those people with acute HIV infection—the first few weeks of being infected—seem to be more infectious. Also, their symptoms are nonspecific in nature, and it’s unlikely the person knows they’ve been infected. It’s estimated that as much as 40 percent of HIV transmission events occur from people with acute infection.

“People with acute infection are generally invisible. If they’re invisible, how can you do prevention on somebody invisible?” Dr. Cohen said.

Also, while scientists have a good grasp on transmission vectors like mother-to-child infection and needlesticks, transmission by sexual intercourse remains a vector with a lot of variables. “There’s a national study in Africa of boys and girls of different ages, and the prevalence of HIV. When you look at a 15-year-old population, there’s a low prevalence of HIV in boys and girls. But as time goes by, by the time a girl gets to be 21, just about anywhere in Sub-Saharan Africa, she’s got about a 30 percent chance of acquiring HIV. That’s unbelievable. If that was going on in the U.S., everything would stop,” Dr. Cohen declared.

“When you interview these girls to try and discover how they’re getting HIV at this alarming rate, they don’t have more episodes of intercourse than American girls,” he added. “They don’t have more anal intercourse, at least according to their history. They’re doing nothing different than American girls. So, there’s something we really don’t understand about Sub-Saharan Africa. Certainly we know these girls are more likely to run into a man who’s infected. A girl in the United States has a 1 in 10,000 chance of having unprotected intercourse with a man who’s infected. A girl in Sub-Saharan Africa probably has a one in ten chance. There is something we don’t understand about this very devastating point that we really need to understand in our lifetimes.”

Windows of Opportunity

There are four windows of opportunity that physicians have to intervene in preventing transmission of HIV: before transmission, at the transmission event, immediately after exposure and after the person has been infected.

“First, we spend most of our time trying to keep people HIV negative. The unexposed person should not become exposed,” Dr. Cohen said. “To do that, we’ve had massive campaigns worldwide. The abstinence campaign, behavior change, condom programs, needle exchange—all designed to keep you from getting exposed, or to keep you from getting an STD so you won’t contract HIV readily at time of exposure.”

All of these method work, however, they all have weaknesses. Condoms only work if they are used every time. Circumcision works, but it takes a lot of effort to become circumcised if you are not already. Abstinence works, but it is impossible to keep people abstinent forever, Dr. Cohen said. And monogamy works only if both partners in the relationship are monogamous. Many of the transmission events in Africa are occurring when a woman in the relationship is monogamous and not using protection because she is trying to have a baby, and the man is not monogamous. “These are called discordant couples and they are playing a substantial role in driving the epidemic,” Dr. Cohen said.

The Moment of Transmission

The second window where researchers can intervene is at the moment of transmission. “You tell your children and your patients, don’t get exposed, don’t get exposed, don’t get exposed. But then they are going to get exposed,” Dr. Cohen said.

“With the transmission event, there’s a window where the virus is invisible,” he said. “Its copy number is too low for you to see. Then there’s ramp-up viremia, where the virus becomes visible. During ramp-up viremia, some of the viral particles get into cells and form a latent pool. We know how to get rid of other pools in replicating cells. In all compartments of the body, we can deal with HIV replication. What we can’t deal with is this latent pool. What renders HIV an incurable disease is this latent pool.”

That latent pool is and will continue to be a high-focus area for HIV scientists, Dr. Cohen said. “The next generation of scientists, they will work on the latent pool, and they will make a contribution,” he said.

There are three general ways that the transmission event can be stopped or blunted: modify innate immunity, create a vaccine or use antiretroviral therapy. Currently scientists do not know how to modify a person’s innate immunity, Dr. Cohen said. As for vaccine strategies, the theory is strong, but nothing has yet been successful.

Animal models have shown that preexposure prophylaxis with ART has been successful in preventing transmission, and it is now being tested on humans. “There are 21,850 people enrolled in clinical trials designed to prove that preexposure prophylaxis will prevent an HIV transmission event. The first trial results should be available in 2010,” Dr. Cohen explained. “The problem is how do we employ those pills? Who is going to take those pills? We can’t put the species awash in antiretroviral drugs, and are there going to be complications and side effects that we don’t yet recognize?”

The third window is post-exposure prophylaxis, where a person is given ARTs immediately after exposure. “If you’re going to use post-exposure prophylaxis, it’s a big emergency and you need 28 days [of therapy],” Dr. Cohen said. “It’s a very special time and we need a lot more effort to make sure people who need this get it. In the U.S., this is a modest problem, in Africa there’s a rape every 7 minutes, and the prevalence of HIV is high.”

Treating Our Way Out

The final window—the one where the majority of funding is directed—is at treating HIV patients with the belief that treatment will lower a patient’s viral load and make them less infectious. There is currently no definitive proof that this is true, Dr. Cohen said. But, if an ongoing NIH study is successful, that might change. The multi-country randomized trial called HPTN 052 was designed to address two questions: is it good to start antiretroviral therapy earlier in a patient’s course, and does treatment help prevent transmission.

“We’re enrolling 1,750 couples, and the endpoint is the partner, not the person receiving the drug,” Dr. Cohen said. “You give the drugs to the patient, you follow the partner, and that person will not get HIV.” The study will last for six years to prove whether there is a durable benefit and should be pivotal in proving or disproving the belief that treatment can lower transmission rates.

“I will tell you that there is a tremendous belief that this works; so great a belief that some people don’t want to wait for the trial results,” Dr. Cohen said. “This comes up in utopian modeling. You can make a model where you can make almost anything happen if you make the right assumptions.”

Such a model was recently printed in the January 2009 issue of The Lancet, which showed that universal HIV testing followed by immediate antiretroviral treatment would put a stop to the epidemic.

“You treat everyone in Africa today. You treat regardless of CD4 count. No more rationing of drugs, and the epidemic will go away by 2020. If this really happened and the model’s correct, then treatment is the solution to the problem,” Dr. Cohen said. “But already you can see the problems. We don’t have enough drugs; we don’t have enough personnel; we don’t know how to find the patients.”

The World Health Organization will be sponsoring a summit meeting this month to discuss the model and its strengths and weaknesses.

“On the one hand, I think this is right. On the other, I think it’s important we prove it,” Dr. Cohen said. “Because if we’re wrong and we put the species awash in drugs, it’s going to take a long time to take a step back.”