Harvard Public Health Review
Summer Fall 2006

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HIV AIDS

HIV-AIDS at Year 25: A Tale of Two Worlds

In the global battle against the virus, Africa was left behind. But innovative drug and vaccine research led by HSPH is helping to save lives.

It was a quarter-century ago, in 1981, that the U.S. Centers for Disease Control and Prevention reported the first case of the disease now known the world over as acquired immune deficiency syndrome, or AIDS. Since then, science has succeeded in holding the disease in check for those who have access to costly drug therapy. But in the developing world--most notably Africa--millions are dying, and drug-resistant strains continue to emerge.
What might the next 25 years hold?

Recently Newsweek Chairman and Editor-in-chief Richard Smith explored that question with a researcher who has fought HIV/AIDS on the frontlines since the virus first emerged: Max Essex, director of the Harvard School of Public Health AIDS Initiative and the Botswana-Harvard AIDS Partnership for Research and Education, and the Mary Woodard Lasker Professor of Infectious Diseases. Essex and Smith, who is a member of the HSPH AIDS Initiative's international advisory board, met with HSPH supporters and friends in Boston last spring to discuss progress against HIV in clinical trials, the School's model partnership with Botswana's government, and Essex's hopes for drugs and vaccines. What follow are excerpts from their conversation, edited for clarity by Essex.

Richard Smith: Max, we seem to be living a tale of two worlds with HIV/AIDS. In the developed world, it's no longer an automatic death sentence. In the developing world, the disease rages on. Why?

Max Essex: In the West, a big breakthrough was the recognition of three-drug combinations that worked very well to save lives. Immense dedication soon emerged to using these drugs, to getting people tested, and to educating those who need treatment most.

In the developing world, most of those very expensive drugs still aren't available. Testing isn't available to decide how best to treat people. Off-patent drugs are available in a few places, but the education and the political will in many countries--the Republic of South Africa, a relatively developed country for Africa, being the prime example--simply hasn't been there. Many African governments haven't yet addressed this crisis in a sufficiently serious way. Africa has been left way behind.

Smith: Is there something about the virus itself that leads to high infection rates in Africa?

Essex: Absolutely. Viruses in Africa that cause HIV/AIDS are essentially different than those in the U.S. and Europe. The main virus in the U.S. and Western Europe is called HIV-1B. B is also present in Africa, but in very low numbers.

The virus most prevalent in southern Africa is HIV-1C. It's undoubtedly more virulent than the other viruses--even those in sub-Saharan Africa, East Africa, or West Africa, where infection rates aren't as high. The medical dictionary defines virulence in two ways: transmissibility, and how fast it kills you. The AIDS virus in southern Africa doesn't kill you faster, but it's transmitted more efficiently.

Smith: Can B and C be treated with the same drugs?

Essex: People in Africa have responded well to existing drugs. But drug resistance develops sooner with HIV-1C, when, for example, you use the drugs one or two at a time--as is often done to prevent mother-to-infant transmission--instead of using three-drug combinations.

Smith: Let's talk about the mother-child transmission issue.

Essex: There has been a lot of progress. By using just one relatively inexpensive drug, AZT (also known as ZDV), you can reduce the risk of transmission of HIV from mother to infant by 66 percent, provided you do it four to six weeks before delivery. If you use another drug, either on top of AZT or alone, or use it only at the time of delivery--sometimes you don't see the woman until she comes in for delivery--you can still reduce transmission by 50 to 75 percent. There are combinations of drugs that can reduce it by 80 to 90 percent and are not too expensive, but you must identify the women soon enough.

Unfortunately, drug resistance then develops in about 40 to 50 percent of the mothers. So if they later need triple-combination drugs to save their own lives, those drugs often won't work if they contain one or more from the class used to block mother-infant transmission.

So there is both good news and bad. We can certainly prevent two-thirds of mother-infant transmission. That's important in Botswana, where 35 to 38 percent of pregnant woman are positive and 30 to 40 percent of the infants born to those women get infected. If nothing is done, one out of every six or eight children will be HIV-positive. But we have to develop new systems to keep the mothers alive so their children aren't all becoming orphans.

There are well over 10 million AIDS orphans in Africa today. About two-thirds, or 65 percent, of recent HIV infections are in Africa. About 80 percent of deaths from HIV are in Africa, simply because they don't have the drugs. But what we can imagine doing in the future is treating a lot more people. Maybe a few hundred thousand people have now been treated with anti-retroviral drugs, and that's way below the goal.
Smith: A few hundred thousand out of how many?

Essex: Out of 26 million infected Africans. Perhaps 10 million of them would be on drugs if they were in the U.S. But patients in the developed world are treated with drugs very early. I think one or two million in Africa will be in treatment in another year, and four or five million within five years, if things go well.
But then we're going to face newly emerging drug resistance. Which additional drugs do we use? How do we cover toxic side effects? Will the expertise be available to deliver treatment to that many people? We need to find better solutions than just drug treatment, such as a successful vaccine, or microbicides, or some other biological means of prevention.

Smith: You and your colleagues across the board have been working for 15 years on a vaccine. Why haven't we seen one by now?

Essex: HIV has two qualities that make it more difficult to cope with than other viruses, even avian flu. HIV mutates fast and can hide in your DNA the same way a herpes virus can hide. It can then pop out when your resistance drops or you stop drug treatment. This tremendous rate of evolution causes problems for vaccine development. We've tried using the same techniques we used with polio, mumps, and measles. They didn't work. More advanced approaches are still being tried, but we're also now working on a whole new generation of vaccines. Anything we've done before doesn't come close to the level of sophistication needed to handle this virus.

I really do believe we will have a vaccine in 10 or 20 years. But 10 or 20 years is a long time, and even a good vaccine won't be enough to eliminate the disease. We've had a great vaccine for hepatitis B for 20 years, but the disease still kills many people in Africa and Asia. When we do have an HIV vaccine, I think we'll have built-in solutions about how to make vaccines for some types of cancers and for other latent infections, such as herpes. We'll know how to make vaccines for a wide variety of things we can't make vaccines against now. HIV vaccine research is building a new science of vaccinology that will be immensely important in the future.

Smith: Tell us about some of the clinical trials you're working on now.

Essex: We're in the midst of a trial with 650 people in Botswana testing six different drug regimens and different methods of ensuring compliance to the treatment. The results are examined by our Data Safety Monitoring Board, which includes people in Botswana who discuss these results with the Ministry of Health and decide whether or not to modify the national program for AIDS.

As a result of our studies, Botswana has modified treatment three times: first, in response to our findings that we could reduce mother-infant transmission if we started one drug two to three weeks earlier than was formerly done; second, when we found that giving one drug to the infant at the time of birth rather than to the mother saved the mother from a drug-resistance problem so that she could later be treated successfully with some of the same drugs; and third, by determining which drug combinations work best for the treatment of adult AIDS patients.

Botswana's government and Ministry of Health have been absolutely splendid in listening and responding to whatever results we have.

Smith: The Harvard School of Public Health approach involves real collaboration with government officials, not only in terms of informing them, but in training their researchers and bringing them into your program.

Essex: Yes, we've been fortunate to have the support to train people from Botswana. We've also been fortunate to have bright, young physicians and scientists from the U.S. with training in infectious diseases who want to go to places like Botswana and spend a year or two participating in and running these trials.

That has worked to everyone's advantage. In 2007, we're going to start a program for Harvard undergraduates who will spend a semester in Botswana for academic credit. They'll spend time in our lab here in Boston, then spend a semester on a research project in Botswana and also take a course or two in African history or languages at the university there.

If you had asked me about doing something like that 10 years ago I would not have been quite as interested, because I would have thought we would have solved the AIDS problem by now. But there's no way we're going to solve it completely in the next 10 or 15 years. These trainees will have a big role to play.
Smith: The work you are doing in Africa has connections to the work in the U.S., correct?

Essex: Absolutely. When we did our first vaccine trial in mid-2003, it was the first trial approved by the Food and Drug Administration to begin simultaneously in a developing country and in the U.S. Not only that--it was the first such trial in the world that enrolled only volunteers who had the right genetic ability to be able to respond. And that could only happen because of the level of expertise Botswana had developed to do 5-digit PCR HLA testing, which is the same kind of tissue typing you do for someone getting a kidney transplant. We could do that level of testing in three or four days on site in Botswana to decide who to enroll in the vaccine trial. So the trial began simultaneously in Boston, Botswana, and St. Louis.

Smith: One of the things that has really impressed me is that the Harvard School of Public Health's AIDS Initiative is not just doing laboratory research. You are also doing research on the ground to examine how treatments work, and you are doing training.

Essex: That's right. Ric Marlink, the senior member and executive director of the HSPH AIDS Initiative, developed in Botswana a system to train physicians and nurses to use antiretroviral drugs. As of six months ago, 900 physicians and 4,000 nurses had been trained to get government certification so that they can write prescriptions for anti-retroviral AIDS drugs. This sort of teaching makes a big difference.

In sub-Saharan Africa, perhaps 5 percent of the people who need antiretroviral drugs are getting them. By comparison, in Botswana the best estimate is about 50 percent--and within the city of Gaborone, where the hospital and HSPH–Botswana lab are, that figure is as high as 75 percent.

Smith: What elements of the Botswana model are you trying to push out to the rest of Africa and to Asia--India, China-- with their growing problem? What will you do to encourage that movement to other countries?

Essex: We are making available to many countries all the educational material used to train physicians and nurses. That's a start.

We are doing similar trials in several other countries in other regions in Africa, and exchanging AIDS experts with other countries. For example, we have an exchange program where people from Tanzania can go to the Botswana lab to learn techniques to bring back to their country.

Recently we were asked by the Southern African Development Commission, an organization of 13 countries in southern Africa, to put on a three-day course on HIV/AIDS for parliamentarians, ministers of health, and other ministers of appropriate governmental activities. The countries included the Republic of South Africa, Zimbabwe, Namibia, Malawi, Mozambique, Tanzania, and others in southern Africa. I first spoke to the group last December, and they've invited us to do a longer course this fall.

Question from the audience: What is the danger of the HIV-1C virus infecting the United States population?

Essex: We are obviously not at risk of an epidemic anything like the one in Africa. On the other hand, I think there is some risk, certainly in the long run, for viruses that are more readily transmissible than those we have here in the U.S. And in fact, there are a couple of recent reports of this in Minnesota, where some cases of HIV-1C have been detected.

The virus traveling fastest in China is partly B and partly C. The virus in western India is C, probably acquired from Mozambique and the east coast regions of southern Africa. I think that, 25 or 50 years from now, new HIVs will have evolved and displaced B, C, and the other viruses that are now endemic in the world.

Q: How are countries wrestling with prevention?
Essex: Prevention using condoms or abstinence can be controversial. But we are in a new generation of microbicides. First-generation microbicides were used vaginally to kill viruses, but they did more harm than good because they were broad-spectrum compounds developed for any sexually transmitted disease and they caused irritation of the mucous membranes. But now there is a generation of oral microbicides that are being tested for their ability to block sexual HIV infection.

I think if we had affordable drugs that blocked infections, weren't very toxic, and women could use orally--so women wouldn't have to negotiate condoms or vaginal suppositories--that would be a real advance.

Q: How can business become more involved in Africa's HIV/AIDS epidemic besides supporting research and organizations like Harvard?

Essex: AIDS drugs are made in Brazil, Thailand, China, and India. This type of activity has barely begun in Africa. The level of action and care in India happened largely because pharmaceutical companies were already there and they could get some sort of blessing from the government.

The first group in all of Africa that really took the bull by the horns to provide meaningful services for any population was the Botswana diamond company. The next was the Anglo-American gold division of DeBeers. They decided they'd invested so much in their employees that they couldn't afford to have them die in their 30s.

Q: Why is it important to do AIDS research in Africa rather than just here in the U.S. and the developed world?

Essex: Africa is the best place to do research, not only because the problem is greatest in Africa--for all the humanitarian reasons that implies--but because the fastest and easiest way to solve the problem is in the population with the highest incidence. If your rate of infection is 10 percent in 18- to 22-year-olds in southern Africa and it is 0.1 percent in the U.S., you can obviously get much faster answers, and do it more cheaply, in a smaller population of people in Africa. If you want to find out what works in women or in infants, you can only do it in Africa. There were no new infant infections of HIV in Massachusetts last year.
It's hard to find money to train AIDS experts from most countries in Africa. We managed to put together a program with people from Botswana, but we don't have money to train people from other countries, such as Zambia or Malawi, for example. A lot of people in those countries will need training if they are to make the kind of progress Botswana is making.

To learn more about advances in HIV/AIDS research and training made possible through the HSPH AIDS Initiative and the Botswana-Harvard Partnership for AIDS Research and Education, visit www.aids.harvard.edu.

This page is maintained by Development Communications in the Office of Resource Development.
To contact us with suggestions, comments, and questions, please e-mail: editor@hsph.harvard.edu

Copyright, 2006, President and Fellows of Harvard College