May 2004

The Real Obstacles to Treating AIDS, Malaria, and Tuberculosis in Developing Countries

Amir Attaran
Royal Institute of International Affairs

Patents are sometimes thought of as a barrier, but usually they are not. There are about 319 medicines currently on the WHO essential medicines list; 291 are true medicines. Only seventeen currently are patented anywhere in the world, of which thirteen are HIV/AIDS medicines. You can then query how often those 291 are patented in sixty-five countries. We found, in those 19,000 cases of a given medicine in a given country, a patent exists 1.4 percent of the time. The bigger countries or the more economically significant markets most often have the patents. The middle-income countries, or the big economies--South Africa, Brazil, and Mexico, for example--have the greatest number of patents. Burkina Faso, Senegal, Chad, and Malawi are not very likely to have patents, although they do in some cases. Activists are wrong to say patents are a barrier in many developing countries to accessing medicines, especially since they only exist 1.4 percent of the time. When the industry has said patents are necessary to protect intellectual property rights on a global scale, that is absolutely wrong.  Because in many least-developed countries, the option to patent has been there for years or decades without being exercised.  We found that companies decided to forego the option about 70 percent of the time.  Where we confirmed that a country had a patent law that could have been used for a given medicine, it was not used.
 
I am worried about fixed-dose combinations. This is an area where I absolutely believe that patents are imposing a barrier. To make fixed-dose combinations or co-packages of medicines for HIV/AIDS, you need the consent of at least three companies in most cases. The existing fixed-dose combination that has generated so much controversy is a combination of medicines from three different companies, one of which is hardly patented at all in the developing world.

The barrier arises because unless these three companies agree to a collaboration, they could not do what India has done and co-formulate their products into a single pill. Minor pharmaceutical companies in India with the market capitalization of a few hundred million dollars have just beaten multibillion-dollar companies to the post on an important invention--that is a problem.

It would be nice to see the industry not simply try to match this effort, but to use its superior technology and innovative ability to make the next generation of fixed-dose combinations or co-packaged medicines. The pharmaceutical industry has lost round one of this struggle.  It cannot be said that the pharmaceutical industry is irrelevant--its technologies are tremendously vital to global public health.  But I have not seen it deploy all the energy it can, or should, in the direction of making simplified AIDS treatment available. I am gravely concerned about the situation.

Donald Roberts
Uniformed Services University of the Health Sciences

In the absence of insecticides, the first line of defense against malaria is the use of drugs. Through this emphasis on reducing reliance on the use of insecticides in seven countries of Central America, they have increased the distribution of drugs by 682 percent since 1991. That translates into an average number of curative treatments per diagnosed case in 1991 of 17.2 complete treatments for each diagnosed case. In 2002 these countries distributed on average 117 complete treatments for each diagnosed case. This is referred to as pharmaco-suppression. 

The statistics for these countries are rather impressive. They have reduced the amount of malaria in those seven countries by 63 percent. We learned fifty years ago that you do not carry out programs of mass drug distribution for control of malaria because as soon as you do, you start exerting pressure for drug resistance in the malaria parasites.

We are now seeing 10 to 29 percent of all cases in Guatemala not responding clinically to the treatment of their cases with chloroquine. Pharmaco-suppression leads to immunity to the parasite, but it creates something else--asymptomatic carriers of malaria parasites. That will increase the number of infected people in the Central American countries--individuals who often come to the United States.

Nicholas Eberstadt
AEI

The official numbers suggest that there are just slightly fewer people in India than in South Africa living with HIV, about 5 million. What is promising is that the Gates Foundation has committed substantial resources to HIV prevention. In the infelicitous phrase, they are going to partner with India.

China looks like a fantastic success story, because the Chinese government announced last month that a total of 697 people had died of all communicable diseases in the first quarter of that year. Why does the Chinese government come up with this wonderfully happy calculation? Well, one reason is because the Chinese government does not test people on a routine basis. Just a few weeks ago the Chinese government took what for it is a big step. It said they will pay for AIDS testing in what they believe to be the worst afflicted areas. So maybe we will have a little bit better impression of the nature and scope of the problem soon. The Chinese government will not embrace and will not join the battle until they see this as an economic threat. As long as it is a humanitarian threat, any number of people in addition to those 697 can die.

The Russian government estimates that a cumulative total of three hundred thousand people have been infected with HIV since the 1980s.  This is a pre-scientific registration system that they maintained in the post-Soviet era, and the only question there is what sort of multiple of this number one wishes to use. The Russian Ministry of Health has a unit of five people for all STDs, and two of those people do not deal with HIV. Like some parts of sub-Saharan Africa, Russia's life expectancy today is no higher than it was forty years ago. What one is hearing now anecdotally in Russia, because this is not being tracked systematically, is absolutely astonishing prevalence levels for STDs in parts of Russia. What this suggests as a sort of a leading indicator is that a problem may be under way in Russia which even some of the outsiders who are actually paying attention to this have not fully grappled with yet.

Richard Tren
Africa Fighting Malaria

Certainly in Africa, the lack of government commitment to delivering drugs happens on various levels. Sometimes it is simply through incompetence, but in other cases it seems almost like governments are willfully attempting to block access. But nevertheless, we have known about AIDS for a long time in South Africa, and all the while the government has done nothing to build the infrastructure. Instead, and very worryingly, it has done almost everything to alienate any kind of partner that could work with us.

Very often, drugs that have been registered for use in the United States, the EU, and Japan wait for, on average, thirty-nine months under the South African Medicines Control Council procedures. The various medicines control councils and medical bureaucracies in Southern Africa are supposed to have been harmonizing their procedures, streamlining their organizations, and reducing costs and time delays. But they have actually been going in the opposite direction. One can argue about the value and the need of the strong medicines control councils, but it is increasingly clear in South Africa that this kind of medical bureaucracy is just an expensive blockage in delivering safe and effective medicines.

The South African government thinks that South Africa and the market for medicines are somehow exempt from the laws of economics. There is no way that these drug pricing regulations can go ahead without reducing the availability of drugs in South Africa. Perhaps more importantly, these strict rules on markups and fees that distributors, wholesalers, and retailers can take would ensure that drugs would only be available in urban centers and wealthy high-volume pharmacies, and that in rural areas and in low-volume urban retailers and pharmacies, drugs simply will not be available.

When it comes specifically to health care, we certainly need more investment in diseases that affect Africa and investment in Africa. One of the problems is, though, that in South Africa in particular we have an exodus of investment. Since 1994, around thirty innovator drug companies have closed down their manufacturing plants in South Africa. Certainly in South Africa and internationally, there is a perception that Africa should be a no-profit zone for companies.  And I think this is very damaging.  Companies can make a profit in Africa, and they should make a profit.

Carol Adelman
Hudson Institute

Drug prices constitute about 20 percent of all of the costs of treating HIV/AIDS. The recent South African plan is one of the few plans that have actually estimated the cost of the doctors and clinics, and they are showing it at about 20 or 22 percent. So you have to ask yourself how is it that we have had the major attention over the last three or four months just on the drug pricing when there are so many other issues involved.

In our study, the patented drugs on average cost $404, and the average copy drug was $449. Almost all the innovator companies will include transportation from the site of manufacture to the country in the price, whereas the non-innovator companies do not. So we feel to really be correct in comparing them, we have to add about 10 percent on. Including transportation, the average patented drug still costs $404, but the average copy drug rises to $497. Eight of the patented drug prices are all lower than the average copy drug price, plus the 10 percent for transportation.  Four of the patented drugs are somewhat higher than the copy drugs, but not by that much.  Nevirapine is significantly higher priced, but the manufacturer actually provides that drug free of charge to mothers in their third trimester of pregnancy to prevent mother-to-child transmission. Nevertheless, it is a high number, and that is probably what figures into some misleading statements about the Indian copy drugs being one-quarter to one-third the price of patented drugs.

The average of fixed-dose combination drugs for patented drugs was $659 and for the copy drugs was $1,296 (both including transportation). There are really only three drugs [Lopinavir + Ritonavir; Abacavir + Lamivudine + Zidovudine; Zidovudine + Lamivudine (Combivir )] where you can compare patented prices to copy drug prices. The patented drug price on the first double combination drug is $500, versus $2,168 and so forth. For the last five drugs, average copy drug price ranges from $113 to $353, but there is no existing patented drug for those copies. Herein lies the debate. The two Indian drugs (two fixed-dose combination drugs) that the Clinton Foundation is recommending, even on the Medecins Sans Frontieres price list, even without transportation, are priced at $270, nowhere near $140. It is very important to know that trimune and triviro are made with lamivudine, stavudine, and nevirapine. The problem with this fixed-dose combination drug is they decided to put these three drugs together. The bulk of the studies show that any combination with the nevirapine is not as effective as with efavirenz, the drug that substitutes for nevirapine. Also, there is definitely more toxicity with nevirapine.  It has been put on the FDA Medical Product Alert List. That does not mean that it cannot and should not be used for the mother-to-child transmission, but it must be used carefully.

Governments are actually paying even more than what is on the price list for the fixed-dose combinations (trimune and triviro), not even including the customs and the transportation. The $140 price does not seem to be in existence, and it is very misleading because it does not help us get to the real obstacles.

Scott Gottlieb
Food and Drug Administration

Are fixed-dose combination drugs good for Africans? They do have an important place, but they are not the entire solution. The problem is that the goal so far as has been articulated, is that the underlying faith here is to get as many people started on treatment as possible. It is not to get as many people as possible on successful regimens as to get as many people started on treatment.  And so the search has been for a one-size-fits-all pill, if you will.  If you want to get a once-a-day single pill, you have to use nNRTIs, non-nucleoside reverse transcriptase inhibitors, and NRTIs, nucleoside reverse transcriptase inhibitors, and you have to combine those, because those do not need to be refrigerated and generally they are probably easier to get into a single-pill formulation. You want nevirapine, the drug that is not toxic to the fetus and can prevent maternal-to-fetal transmission. There are certain things that you have to accept with these choices: First of all, nevirapine is highly toxic. Seven percent of people get a rash on the drug; 1 percent of those people will develop Steven Johnson Syndrome. The drug is toxic to the liver: between 10 to 20 percent of patients will develop abnormalities with their liver function tests. Do we need to accept that morbidity and mortality? Does the benefit of starting three million people on HIV therapy outweigh the benefits that might come by having more options available and being able to tailor regimens a little bit more and perhaps get people on successful therapy and be able to withdraw therapy if people start running into trouble? We also need to be honest about where we draw the line on how much morbidity and death we are willing to settle for just from the treatments themselves. In the West, we do not start people on drugs when you know 1 percent or 2 percent are going to die, except in horrific circumstances.

Are the Indian counterfeit drugs good fixed-dose combination drugs for Africans? You have to look at the quality, bioavailability, and toxicity of the drugs. These are not questions that we can answer today, because no one has seen the data from the Indian companies. Did they get these three drugs together in the right way where it is going to be stable and not turn to mush in the heat and humidity of the African environment? These questions can be answered, but they have not been thus far.

Are these fixed-dose combination drugs cheaper than their branded alternatives? The $140 price does not exist. It has never been actually quoted to anyone who wants to make a purchase. Price availability and having easy options that could be widely distributed are important. There are ways to achieve all those things without settling for options that are untested and do not solve all of your problems. Price as the only metric is unlikely to lead us to good public health solutions here.

Abner Mason
AIDS Responsibility Project

The United States is about to embark on a $15 billion program.  Almost half that money is going to be for treatment, and a huge portion will go toward buying drugs.  So the issue is: do we buy drugs that we know are safe, or do we take a chance? There is a good, sound argument that when you are in an emergency, you ought to take chances, you ought to take risks if they are absolutely necessary. But if you do not have to take a risk, then you should not. The challenge we face in the short term--the next year to two--in implementing the emergency plan is neither a funding problem nor a price problem. It is really an infrastructure problem.  Our challenge is how are we going to deliver treatment to people who live in places that frequently lack electricity, running water, and health infrastructure--either physical structures like hospitals and clinics or health care workers, nurses, and doctors. How do we implement a program of this complexity? That is the challenge we face.

A resolution I offered asking the president to direct Ambassador Tobias and his team to buy drugs that have been tested was passed unanimously by the President's Advisory Council. There should be no double standard; Africans deserve drugs that are as safe and efficacious as we would give to the people that we love here at home. And we can afford to have that standard.

All of us should try to change the dynamic or the discussion about the role of research-based pharmaceuticals. The only good thing that has happened in this twenty-plus-year epidemic is that we now have drugs that work. We owe it to the people who are on therapy now; we owe it to the millions of Africans who are going to be put on therapy under the president's plan; we owe it to them to do everything we can to create an environment where new drugs will be created. Almost everyone who is on an anti-retroviral today is, at some point in the next one to five to ten years, going to become resistant to the drugs. We need new drugs.  We need them quickly, we need a whole battery of them. And there is really only one way we are going to get those new drugs: the research-based manufacturers have to stay in this therapeutic category.  We need to find a way to change the debate so that the question that we are asking ourselves and that policymakers are asking us is: how do we incentivize research-based pharmaceutical manufacturers to stay in this market?  How do we make it attractive for them?  How do we make it profitable for them?  How do we make it a therapeutic category that they want to stay in? We have to recognize that there is no cure on the horizon for this disease.

The whole situation around global AIDS has dramatically changed in the last year and a half since the United States decided that it was actually going to lead the effort to fight global AIDS. Sixty-five million people infected; 20 million have died; approximately 45 million people live with HIV today.  More than half of those live in sub-Saharan Africa.  Every year about 3 million people die of HIV, while about 6,000 people die each day. And every day, according to the UN, there are 17,000 new infections. As horrible as it has been, the worst is yet to come. The good news, though--and it is something that we should not forget as we wrestle with the implementation of the emergency plan--is that our country has finally stepped up and decided to lead. So this is a large new foreign aid commitment that our country is making.  It is a wonderful story of compassion and generosity and ingenuity. It is really important for us to find ways to make sure that we are telling the American people this story. No nation has ever tried to do something this complex.  So we need to be patient with each other, patient with our government. The American people need to understand what their country is doing, what they are doing, because it is the reason that we are here and it is the reason why there is hope where once there was only despair.

AEI research assistant Sharon Utz prepared this summary.