Breaking The Silence: From Here to Africa and Back

The XIII International Conference on AIDS, with its theme "Break the Silence," was the first in history held in the Southern Hemisphere, on a continent with millions infected, orphaned, sick or dying. It is a home for countries where, in the words of the vice president of Malawi, one of the sub-Saharan democracies most impacted, "it is not a question of losing a generation but of losing the nation." The message is simple:

Africa is dying.

The questions asked in Africa are important to us all -- they are the same questions we need answered here. When is it necessary to start drugs? Which drugs are the most effective to use? How can we minimize the use of antiretrovirals without compromising the health of people with HIV? What do we do when the drugs fail people? And one more question -- the biggest in the world, but unique to the poor countries on earth: How can we get access to these drugs?

The ambiance of the South African host city of Durban made those of us from the United States realize constantly that we were on a continent unfamiliar to most Americans.

Durban is in KwaZuluNatal, where instead of hello we heard "Sawubona -- Welcome to the Kingdom of the Zulu." Occasionally we heard people make tongue clicks -- sounds that have tones as distinct as our vowels. We were often surrounded by flat-topped Jacaranda trees and in front of the convention center sat fat-bottomed, small-headed Baobab trees. Lounging on the green lawns of the University of Natal, in whose dormitories many of the delegates stayed, were exotic birds with long curved blue beaks. There were vistas overlooking the busy seaport. Trees whose leaves looked like long green dreadlocks spread out like a jester's hat that made us smile when we saw them. Dozens of monkeys were waiting on the pathways in hope of food.

The real work of this conference began with an invitation to the community indaba sessions. Indaba means meeting or getting together. Hundreds of delegates from around the world, including many from the United States, attended these sessions that attempted to teach activists how best to use the presentations, how best to understand the science. Africans like Dr. Salim Karim Abdool (the scientific chair of the conference) led these sessions.

Even the clothing told us that we were in an international setting. Brand names like Inkulu, Indali, Groot Uitverkooping. There were Kani jeans. What do they all mean? Probably pretty much what Hilfiger or The Gap means in the USA. And the ways of thinking were as diverse as the clothing.

The Official Opening

The international meeting on AIDS began with a march through the streets of Durban with thousands of people, hosted by both the South African AIDS activist group "TAC" and the New York-based American international activist group, the HealthGAP coalition. The leaders of the march handed Peter Piot, who heads up the United Nations AIDS effort, and Tshabalala-Msimang, the Health Minister of South Africa, a petition demanding access for all people to the AIDS drugs available to people in North America and Europe.

Thousands of delegates gathered on the first night at the Kingsmead Cricket Stadium -- a huge field near the conference center. The ceremony began with a black woman singing a capella that life had changed and would never be like it used to be. Behind her, people wrapped in white shrouds stood silently, representing the dead. On a stage in the background sang a chorus of hundreds of people dressed in red, purple, and yellow. Across the foreground ran crowds of young men dressed as warriors followed by children dressed like lion cubs. The drums beat, people started to scream, moved faster and faster, and the ground shook with the sound as if we were having an earthquake. If music, noise and crowds could end an epidemic, AIDS would be over.

Then, amidst the music stood Thabo Mbeki, the president of South Africa. He spoke with a quiet passion.

"We are a country and a continent driven by hope and not despair and resignation to a cruel fate. Those who have nothing would perish if the forces that govern our universe deprived them of the capacity to hope for a better tomorrow.

"The world's biggest killer is extreme poverty.

"Every year in the developing world, 12.2 million children under five years die -- most of them from causes that could be prevented for just a few U.S. cents per child. They die largely because of world indifference, but most of all they die because they are poor.

"For most people in the world today, every step of life, from infancy to old age, is taken under the twin shadows of poverty and inequity, and under the double burden of suffering and disease. For many, the prospect of a longer life may seem more like a punishment than a gift."

President Mbeki outlined the country's AIDS action plan and called on the world community to help. He said that in the context of a world driven by a value system based on financial profit, he assumes that the notion of "human solidarity remains a valid precept governing human behavior."

The conference ran for a week, covering topics familiar to everyone who attends similar gatherings of scientists and doctors, issues regarding treatment and prevention. The difference in the South African conference was a noticeable effort to make material relevant to poor countries. Here are a few of the general subjects covered in great detail during the thousands of sessions.

Starting Treatment

As late as Possible with as Little as Necessary: A new Paradigm

Although it is not at first obvious, the question of when to start treatment affects both rich and poor countries. The conference had many presentations which continue to give us reasons to believe that the correct rule of thumb is to wait as long as possible before starting antiretrovirals.

First, if how long we can use antiviral cocktails is limited both by how many side effects they have and also how long it takes before the virus becomes resistant to them, then it makes sense to use them as late as possible (and as infrequently as necessary!).

This is also the cheapest way to use the drugs, which means that countries without lots of money can spend the least amount necessary.

This is a big change from the idea of "Hit Hard Hit Early," and there are two clear reasons for the change: First, the notion of "eradication" first proposed at the International AIDS conference in Vancouver four years ago has eluded science. It was the hope of eradication that drove most people toward the idea of starting antiretrovirals as soon as it was clear that a person was HIV-positive.

There are several theories on why the drugs fail to eradicate the virus after many years of use. The drugs are clearly not powerful enough, as data shows there is still virus being made by cells at a very low level. This may be the reason eradication failed, or it may be because there are cells programmed to produce virus at some future time that take a very long time before they "turn on" and start making virus. (These are the so-called "latent" cells.)

Either way, without the prospect of eradicating the virus to drive taking pills, and with the growing evidence that drugs cause cumulative side effects such as lipodystrophy syndrome, it is just common sense to use them only when necessary.

There is NO evidence WHATSOEVER from any study that using antiretrovirals early helps keep people healthier longer or alive longer. In fact, there are many reasons to believe that the opposite is true: The longer you are on antiretrovirals, the greater the chance that the virus will become resistant to them, and the more likely that there will be side effects that force you to stop using the drugs and, without question, compromise quality of life.

The ONLY clinical trials -- the only experiments with real people that tested the cocktails for how effective they are in delaying disease progression and death -- were in people with very advanced disease. This means that we simply do not know that using drugs early is helpful.

Many people believe that as long as you have enough T-cells to fight illnesses, it makes no sense to use antiretrovirals. It would seem that in general, people with more than 350 T-cells very rarely get any opportunistic infections and for this reason, starting antiretrovirals before this point, unless one has an opportunistic infection, makes little sense.

From the African perspective, this information is good news because it means that if antiretrovirals are used, they should be used in late-stage illness. This is the least costly approach and minimizes the need for management of side effects.

A Drug Review

Before starting this section, we should review the drugs that are currently available. For those who are rusty on antiretrovirals, here is a short explanation of how they work.

There are two types of HIV drugs that have FDA approval: reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). RTIs stop HIV from teaching a cell how to make more HIV. PIs stop an infected cell that already knows how to make HIV from making functional HIV. RTIs come in two types: nucleoside analogues (nukes) and non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Nukes stop HIV by operating as decoy instructions so that the virus gives the cell bad information on how to make more HIV. NNRTIs ruin HIV's ability to teach the cell anything. PIs ruin the part of an infected cell's machinery that helps make new virus particles.

There are now a total of six nukes, five protease inhibitors and three NNRTIs approved by the FDA. We are expecting many more drugs over the next two years, most of them variations on one or another of the basic types of drugs we already have.

Now, on to the Big Question: Which Ones Are the Best?

This is a very hard question to answer, for several reasons. First, the word "best" might mean "most powerful." Secondly, the answer will always depend on what type of virus you have, and what other HIV antiretroviral drugs you have already taken. Finally, the answer also depends on what future options the particular combination you are looking at might compromise.

Now with respect to the question: As for which drugs are most powerful, unfortunately, we are not yet 100% sure. But the conference gave us some new information that helps.

First, for people who have not yet used antiretrovirals: You cannot know if one cocktail is more or less powerful than another cocktail without trying them out head-to-head in a trial. This means that we really do not know exactly which cocktails are the most powerful. However, one study showed that most of the standard drug cocktails are equivalent when used by people who have never taken antiretrovirals, in terms of keeping people alive and delaying disease progression. It was also shown that carefully choosing a cocktail to make sure that a person can comply with taking the pills on time and to make sure that a person has virus that will respond to the particular cocktail leads to better outcomes. Unfortunately, for most of the world, tests of what drugs might work best are not affordable.

There was some new data presented that has implications for people just starting drugs, whether here or in Africa.

First, it would appear from the latest data that the powerful nuke Ziagen, the trade name for Abacavir, used with two other nukes did just as well, over a six-month period, as a protease-plus-two-nuke combination (the standard against which all cocktails are measured). This is important because the first cocktails that stopped HIV for a long period of time were based on protease inhibitors. If a cocktail can be made without using these powerful protease inhibitors, then these can be saved for later!

This would also lead us to believe that the new "one-pill cocktail" which will be called "Trivir" might be successful. (Trivir is a mix of AZT, 3TC and Ziagen, all of which are nukes.) A one-pill cocktail would also have great benefits, as current 25+-pill-a-day regimens have made adherence extremely challenging. Since the pill is composed entirely of nukes, it saves protease- and NNRTI-based cocktails as a second bite at the apple! This pill would be easy to store, so it would be a great drug for developing countries.

We have also figured out that surprisingly, three old nukes, 3TC plus d4T plus ddI, used together are almost as good a cocktail as a protease inhibitor regimen at getting viral load down and T-cell count up. This may not be true for people with very high amounts of virus, but given how inexpensive it is to make these three drugs (CIPLA, a drug company in India, makes them all very inexpensively, and can produce a cocktail for about 63 cents a day instead of the 33 DOLLARS a day the average cocktail costs in the U.S.) this might be a logical cocktail for countries that cannot afford fancy drugs -- and it buys time.

Finally, there were several presentations of the use of the nuke ddI plus hydroxyurea (a very old drug that seems to make ddI work much better. It is not an antiretroviral). There is a lot of controversy about the use of this combination, although it is certainly inexpensive and seems to do a good job on people who are without very high amounts of virus. Many poor countries are trying out this regimen.

For People Who Have Used up all Their Drug Options Except for NNRTIs

Data was presented in Durban on Abbott's new powerful PI. Up until now, nothing has been able to help people who have had all their drugs fail them. But this new drug, used with the NNRTI Sustiva (a drug made by DuPont), was able to keep the virus very low during a six-month study of people who had failed three protease inhibitors and had used many nukes for a long time. Even taking into account people who left the study, 82% of those who started this treatment cocktail by six months had pushed the amount of their virus below 400 RNA copies (the way the amount of virus is measured). This is pretty good, and a good argument for starting with this drug even if you have never taken a PI. The argument for starting with this drug is a belief that patients are less likely to fail over time when using a powerful drug.

However, a word of caution here: There has been no study comparing this new drug cocktail with the famous double protease cocktail of Ritonavir plus Crixivan or Ritonavir plus Fortovase. It may well be that these "double protease" combinations are just as good as the new drug. There was data presented that shows the Crixivan-Ritonavir combo MAY be more powerful than the Saquinavir- (or Fortovase-) Ritonavir combo.

An African Context for the Question of Which Drugs Are Best

It makes sense from the point of view of poor countries to look at how good it is to use a less-powerful regimen. And here is the big news: It might also make sense for people in rich countries to look at the results, because it turns out that there might be an advantage to sequencing drugs in a way that does not use the most powerful cocktails first.

A technique called "Markov modeling" was used to evaluate the long-term outcomes of different antiretroviral strategies. The amazing result was that using ddI alone first and HAART much later is better than using HAART right away.

The goal of therapy is to give people the longest and best quality of life. Given the side effects of the new medicines and the fact that there is a rate at which the virus becomes resistant to them, a plan that uses a less-powerful regimen at the beginning of treatment is a better plan than starting with the heavy artillery when you don't yet need it.

Poor countries have not yet used many drugs. But sometimes there can be a benefit from not being the first. To begin with, most people in Africa and Asia are drug-naive. This means that the chances a person with HIV will not have a virus that responds to a therapy is very low at present. It also means that poor countries have a public health duty to try to make sure people do not use drugs in a way that leads to widespread drug-resistant virus. Not taking drugs on time is the biggest cause of drug resistance. For this reason, simplification of regimens is very important.

Glaxo has begun testing a two-pill-a-day drug that will be called "Trivir." In India, a similar event took place, with a company called CIPLA producing a drug called "Duovir," which is the same as "Combivir" but much less expensive. Such combinations of drugs into one pill can help make sure people take their medicines on time. This is the single best way to keep the virus from getting through the drug blockade. Studies of Trivir were presented and we fully expect that this drug will be made available over the next two years, if not sooner.

STIs

One of the most exciting things presented in Durban that affects everyone in the world with HIV are the experiments that are beginning at the NIH in interrupting therapy. One group of people is using their cocktail every other week, and so far the virus remains undetectable. This was expected because when people stop taking their cocktails, it usually takes at least seven days for the virus to come back. This would mean taking half as many drugs, reducing side effects and cutting the bill in half. Another group is trying out taking drugs only two days a week. The results are not yet clear for this technique. Still another group is taking their medications every other month. The bad news here is that the virus comes back during the month off. The good news is that after three breaks so far, the virus always gets pushed back down with the drugs and does not show any signs of resistance.

Data was presented showing that during longer "drug holidays," some of the side effects of drugs might be reversed, such as high cholesterol and other fats in your blood.

Nobody should try these ideas out on their own. But everyone should pay attention, for these methods not only will make it possible for more people in the world to get medicines, but may also lead to a much better way for all of us to take the medicines that we already have.

The Future

Much of the conference focused on vaccines and microbicides, but unfortunately there was little to report. Although there are many efforts to develop a vaccine, and much progress in preparing to undertake trials, there is no news that any vaccine shows itself to be effective. We have simply not yet tested the vaccines we have to see if they work. For microbicides, there was news that is not so good. Many of us thought that lubricants with nonoxynol-9 might help stop the virus from infecting a person. It appears from the data presented at the conference that this is not the case, at least not in prostitutes who use it often.

What is more promising is the news about new drugs. There are 37 new antiretrovirals in development. Some we can expect in the next couple years, but the majority won't be developed for a much longer time. A few of them are truly amazing: several appear to successfully stop the virus from getting into cells. These are called "fusion inhibitors." They will be useful for people who have used up all their options. Others are called nucleotide analogues, and appear to be a kind of "nuke" that people who can no longer take other nukes can still use. Other types of drugs that are being studied are PIs that work in a person who has PI-resistant virus, and NNRTIs that work even on virus that has grown resistant to NNRTIs. In short, there are many drugs in the pipeline that are improvements on what we have now.

But there is no substitute for two realities: using the drugs we have wisely and having access to them in the first place.

Companies, countries, politicians, rich men and women, and people of goodwill around the world are trying to find ways to get medicines to everyone who needs them.

Mandela

The XIII International Conference on AIDS ended with a speech from Nelson Mandela. He said:

"A tragedy of unprecedented proportions is unfolding in Africa. AIDS today in Africa is claiming more lives than the sum total of all wars, famines and floods and the ravages of such deadly diseases as malaria. It is devastating families and communities, overwhelming and depleting health care services, and robbing schools of both students and teachers. Earlier this week we were shocked to learn that within South Africa one in two, that is, half of our young people, will die of AIDS. Something must be done.

"We need and there is increasing evidence of African resolve to fight this war. Others will not save us if we do not primarily commit ourselves. Let us, however, not underestimate the resources required to conduct this battle. A constant theme in all our messages has been that in this inter-dependent and globalized world, we have indeed again become the keepers of our brothers and sisters."

As you read these notes, a U.S. Congresswoman named Barbara Lee (D. California) got a bill passed by the House and Senate to provide hundreds of millions of dollars for Africa. It is a beginning. With your help, it will not be the end. There are those who say you do not care about Africa, that you do not care about poor people in far away places.

Prove them Wrong

• Send a copy of this article to your friends.

• Call your Congressperson and tell him or her you support increased funding for medicines to end the worldwide epidemic.

• Tell your friends that you know better than most how bad it will get if this disease is left to spread around the world, collapsing economies that will affect our stock market and mutating to forms that are easier to transmit and possibly to forms that our drugs cannot stop.

• Tell your friends that stopping AIDS everywhere is the only way for everyone to be safe.

• Break the silence.

David Scondras is the founder and chairperson of Search For A Cure. Search For A Cure is a not-for-profit organization providing education, promoting access, and advocating the basic human right to safe and effective treatment for all people living with HIV/AIDS. In 1996, Search For A Cure created the nationally recognized free HIV treatment series Reasons For Hope, now published in over 50 community-based gay and lesbian newspapers across the U.S.

Contact Search For A Cure: 617-536-2474, fax 617-266-0051, www.searchforacure.org, email hope@sfac.org.