Against all odds, treatment for HIV is expanding in Africa and elsewhere in the developing world. Beginning in the late 1990s, Brazil showed the way by making affordable generic antiretroviral (ARV) drugs produced in their own factories available to all of its HIV-positive citizens. By daring to break the monopoly of the multinational patent holder companies, Brazil dropped the average price of a year's therapy from $10,000 to under $600 and made it available for free to 140,000 Brazilians. India's historically flexible patent laws allowed generic drug makers there to export affordable drugs to Africa, where non-governmental (NGO) treatment programs run by organizations like Doctors Without Borders (MSF) soon proved that providing HIV treatment in severely resource-limited settings was feasible and therefore conceivable for African governments to undertake. Competition among the Indian generic manufacturers soon pushed the average price of therapy to under $350 per year then to as little as $140. Thailand followed up an aggressive prevention campaign in the 1990s with a treatment program based on Thai-made generic drugs. Funding from the new Global Fund for AIDS, Tuberculosis and Malaria (GFATM) and other sources have encouraged governments to expand the scope of their health programs. The United States' President's Emergency Plan for AIDS Relief (PEPFAR) has funded another track of treatment, largely based on drugs from originator companies, with prices now reduced to the cost of manufacture. Other treatment programs in Africa, funded by charities, religious groups and businesses, continue to grow, using donated drugs from the multinational companies, heavily discounted branded drugs and purchased generics. The treatment landscape in Africa in 2005 has evolved beyond what many people thought possible just five years ago, yet it still falls far short of what is needed.

Despite the progress, the overall picture of HIV treatment in the developing world is spotty, with only about 12 percent of those who need ART receiving by at the end of 2004. The World Health Organization's (WHO) ambitious "3 by 5 Plan" to treat three million people by the end of 2005 is likely to wind up treating about 1.2 million. Disbursements from the GFATM are lagging. One bright spot is the fast-growing PEPFAR program, which is ahead of schedule in bringing 470,000 people under care by June of 2006.

Although low cost generic drugs made these gains possible, it is becoming increasingly clear that the infrastructure -- the facilities, staff, equipment and supplies -- needed to assure the quality and sustainability of these fledgling treatment efforts is not available at a similar discount -- where it is available at all. And, even as these programs struggle to their feet, economic developments and legal changes in the Indian patent laws that made generic drugs possible, threaten to knock them back down. The continued expansion of ARV therapy in Africa and elsewhere is at risk of collapse unless problems with funding, staffing, administration and drug supply are addressed. Despite the good start, the lives of millions of people with HIV remain at risk unless sustainable solutions to these problems are found.

Proof of Concept

When the multinational drug companies realized what was happening in Brazil they lashed back at the threat by mounting an all-out campaign to defeat the affordable drugs movement. While major pharmaceutical companies like GSK and Bristol Myers Squibb had charity programs for AIDS operating in Africa since the mid-1990s, those programs were largely focused on support for specific medical facilities or services for orphans. If they were available at all, major label ARVs in Africa were priced at the same stratospheric level as in the North or given away with so much red tape that few got them. One of the first obstructionist tactics the big companies rolled out was a whispering campaign to reinforce the conventional wisdom that offering treatment in Africa was a fantasy. Experts knowingly pointed to gaps in African infrastructure, citing the lack of trained staff and clean water (and, bizarrely, even the lack of wrist watches) as insurmountable barriers. Of course, many of their observations were valid and infrastructure is proving a formidable challenge, but the naysayers served a political purpose by implying treatment was futile unless every underlying problem could first be solved. Artificial controversies were sparked that pitted prevention against treatment; that claimed treatment was not cost-effective; that claimed if drugs were dumped on Africa then drug resistance would spread around the world. Against this onslaught a few groups worked to demonstrate that treatment in Africa with affordable drugs and minimal infrastructure was achievable. Their success was a necessary step in convincing northern governments and funders to undertake "3 by 5." It could not have happened without generic drugs.

As the propaganda war slipped away from them, the pharmaceutical companies turned to lawsuits before finally capitulating and grudgingly offering their branded drugs at no-profit prices or through charity programs. It may be that they ceded ground because they realized that the only battlefield that mattered was in the domain of international trade law, where they enjoyed overwhelming superiority.

The big drug companies obstructed affordable generic medicines not because they feared the loss of markets -- there was essentially no market in Africa -- but because they feared losing control of their patent monopolies: their intellectual property. And it was not even intellectual property in Africa that was the great concern, since few companies had bothered to patent their drugs there. More likely they were terrified of seeing the example spread elsewhere. Compulsory licensing in Brazil; generic production in India; the threat of re-importation of low cost or charity drugs from Africa to the European markets were portents of doom. What if consumers in the United States began demanding affordable medicines? It is the principle of ownership, everywhere, with no limits on monopoly control that has been the real battle prize.

Quality Counts

India's generics companies make drugs for the world including the United States. Most of the Indian ARV makers use factories that are inspected by the U.S. Food and Drug Administration (FDA) and its European equivalents. Questions about the quality of Indian generic drugs have mostly been fueled by the multinational companies as part of the campaign to protect intellectual property. But there are legitimate issues of quality that need to be addressed. The WHO maintains a list of prequalified drugs supplied by sources that have been vetted for quality and consistency. Drug regulatory experts inspect the methods and materials that are used to make the finished drug product in pill form. Large government and NGO purchasers look to the list when deciding what to buy.

In 2004, a number of drugs that were certified by the WHO under its prequalification program were removed from the list, which caused ripples of uncertainty in the patient community and titters of glee from the pharma lobby. Some of the drugs were de-listed voluntarily after the WHO uncovered discrepancies in the reports of bioequivalence testing, clinical studies designed to prove that the generic version of a drug delivers the same amount of medicine to the blood that the brand name does. The story goes that one of the Indian research organizations contracted to perform these studies simply evaluated a single patient then essentially photocopied the result to make up the 15 or so tests the study required. Whether the drug company was neglectful or complicit in this fraud is unclear. Nevertheless, the bioequivalence data on all drugs performed by this research company fell under suspicion and several Indian drug makers withdrew their products from the WHO prequalification list until the studies could be repeated and verified.

Prequalification is a valuable status to have. Many government programs are unable to evaluate the quality of drugs and rely on the WHO to identify reliable sources. But the WHO program has its limits. Currently, it only inspects the production of the finished form of generic ARVs but not the factories that produce the bulk drug product, called the active pharmaceutical ingredients (API).

The U.S. PEPFAR program has set even higher standards for the drugs it will spend taxpayer dollars on. PEPFAR says it will only pay for drugs that are good enough for Americans; those that have been approved by the FDA. Generally, the Indian companies don't object to this, seeing FDA approval as the ticket to greater market acceptance. Many critics, however, saw FDA involvement as a redundant barrier erected to protect the U.S. pharmaceutical industry -- after all, the head of its international AIDS effort is the former chief of the Eli Lilly pharmaceutical company. Still, the U.S. government has said that generic drugs will be acceptable to PEPFAR as long as they have been okayed by the FDA. The first of the Indian generic drugs will soon have cleared this hurdle and critics will be watching to see if they will join the brand name drugs dispensed by PEPFAR doctors in Africa and elsewhere.

The Weight

Just as competition among the pill makers brought prices down, having multiple sources of the the bulk active ingredients -- the APIs -- that go into the pills should also produce competition that will reduce prices. Most APIs used in generic drugs are made in Brazil, India and increasingly, China.

The manufacture of bulk drug APIs is measured in tons. For example, a ton of lamivudine will treat about 8,000 persons for one year. If all eight million people who need treatment were to take lamivudine, they would consume nearly 1,000 tons per year. The world's current capacity for the production of bulk lamivudine is about a third of that. Drugs with high daily doses require much more physical product than drugs with lower doses. For example, an individual taking nelfinavir consumes about two pounds per year whereas the yearly dose of stavudine is only about three-quarters of an ounce.

Increasing and sustaining the industrial capacity to produce sufficient quantities of APIs at competitive prices has yet to be addressed. While there is currently sufficient capacity to supply APIs for the drugs most often used in the developing world, that capacity is lagging for badly needed second-line drugs such as efavirenz and tenofovir.

Drugs and More Drugs

The most common generic ARV regimens currently in use in the developing world are based on nevirapine and supported by lamivudine plus d4T or AZT. Although the decision to roll out these drugs was driven by their low cost, the regimens are effective, even if problematic for many. Nevirapine in particular can be tricky. Close monitoring is recommended during the first several months to avoid liver toxicity, especially in women. Many believe that nevirapine is not suitable for people who are taking certain tuberculosis medications. Efavirenz might be a better choice for them, but so far the generic price for efavirenz is no better than the price from the patent holder. Nevirapine is also not very forgiving of interrupted or intermittent dosing and resistance to the drug is quick to appear when drug concentrations are not maintained. When a nevirapine-based regimen fails, there are few good choices in the developing world. Ideally, a switch would be made to a protease inhibitor, such as Kaletra. But the ritonavir needed to boost this and other PIs requires refrigeration, which can't be guaranteed in many settings. A Kaletra-based regimen is far more expensive than nevirapine and there is currently no generic version of Kaletra available. A new generation of Kaletra that does not require refrigeration should be approved within the year, though there is no word on its price yet. If it chooses to get involved in this great effort, Abbott Laboratories, the makers of Kaletra, will be in a position to help revolutionize therapy in resource limited settings.

Tenofovir is an attractive replacement for stavudine or AZT because of its potency and minimal side effects profile. But tenofovir is not yet available from the Indian generic makers and it is questionable if it will be if it turns out to be protected under the new Indian patent regime. Tenofovir is available as second-line therapy in some PEPFAR and other programs, supplied under Gilead's no-profit program for countries that can't afford it otherwise. Gilead has taken steps to increase its capacity to provide the developing world with tenofovir and its fixed-dose combination of tenofovir and FTC. They have recently licensed a South African generic maker to supply the 95 countries in its no-profit access program. As one of the fastest growing ARV makers over the past few years, Gilead can afford to be generous, but one wonders about the sustainability of no-profit pricing in the long run. Voluntary licenses with modest royalty payments to the patent holder would be a better approach, some think. Multiple manufacturers might create more competition and drive prices down by stimulating greater demand for the raw materials. Yet some fear that competition would also increase the incentive to cut corners on quality.

Currently, the no-profit price of Gilead's tenofovir is about $25 a month, which compares to a price of about $3.30 for generic d4T from India. But with reports starting to stream in about d4T-associated facial wasting in Thailand and peripheral neuropathy in Kenya, when does the cost of the cheapest drugs become too great?

We may be seeing the emergence of two tiers of treatment in Africa: PEPFAR, with its newer, less toxic drugs and full service monitoring, and the generic-based programs that use less monitoring and older, cheaper drugs with more side effects. Both are keeping people alive, but one is a rich program and the other is struggling with limited means. If PEPFAR leaps ahead as the largest treatment provider in Africa, the trickle-down benefits may eventually appear in the other efforts as staff is trained and knowledge transferred to more people. But critics charge that PEPFAR is already sucking the life out of some government programs by luring trained staff away with higher pay. Nevertheless, retaining staff is a huge structural problem that is not easily solved. A recent news report claimed that 1,000 nurses leave Kenya each year for jobs in Europe. It could be that a well-to-do program like PEPFAR that pays superior wages may ultimately help keep talent in the country.

The Future

The Clinton Foundation negotiated a breakthrough low price for generic ARVs, but this has not been followed up with purchase orders that would meet the criteria for obtaining this price. Still, the promise to provide a year of ARV treatment for $140 has given confidence to government programs that feared undertaking an unaffordable commitment.

Economies of scale may bring the price of generic drugs down to Clinton levels, even without the conditions of sale required under its cash-on-the-barrelhead terms. But if companies do not receive payment, then they will have little incentive to continue offering their products. Several Indian generic companies have complained that certain African governments are slow to pay and that the cost of bearing this risk must be passed along to their other customers. Also, corruption persists as a problem in Africa. Some countries require a local agent to purchase and receive the drugs for resale to the government. This is an opportunity for big markups and kickbacks to government officials with little transparency of the final price paid for the drugs.

There are still some barriers to reaching the lowest possible price for ARVs -- import duties, taxes, local distributor markups -- but it's not clear that even halving the cost of drugs will increase the numbers treated at this point. Low cost generics primed the pump and made AIDS treatment in Africa conceivable, but even free drugs won't make it into bodies without the supporting infrastructure. In mother-to-child transmission programs, it appears that the cost of providing single-dose nevirapine, a simple protocol now recognized to be fraught with problems, is not much less than sustaining a program to provide more complex protocols, or even continuous treatment. Yet it was the single-dose plan that allowed the bureaucrats and investors to consider treatment in these difficult settings possible at all.

What Could Possibly Go Wrong?

There is reason to be optimistic about the prospects for treating HIV in Africa -- and some say they dare not consider the alternative. Momentum is finally building, but now the course is shifting to difficult terrain. If there is the will to purchase and pay for the drugs, then it is likely that they will continue to be supplied by someone, somewhere. But who is going to transport them, store them, inventory, reorder, and dispense them? Who will pay for training more doctors, nurses, medical officers and peer counselors, more administrators and more accountants? There is a need to educate many more patients and many more educators. There is a need to simplify and reduce the cost of diagnostics; to settle on new guidelines for treatment; find better second-line, third-line and less toxic regimens. There is a need to tackle corruption and to build political will and donor confidence and lift the crushing burden of debt. The cost of drugs may have receded as the main challenge, but it threatens to reemerge if the supply is cut off or if there is a spike in prices due to world economic events. Will donor fatigue slowly strangle the life from the effort? The GFATM donors are already backing away from their commitments. A fragile government's earnest health plans can be disrupted overnight by disaster or war. The PEPFAR dollars could be cut off by the whim of Congress -- and there is fear that the top notch infrastructure erected by PEPFAR will collapse more quickly and completely than more modest, independently established programs. But no matter why or how, when the money stops or the drug shipment does not arrive, the impact will be slow devastation and a slide back into despair.