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A deadly double standard in AIDS treatment

Philip Stevens
Medical Progress Today
July 13, 2007

Among the many unknowns in HIV/AIDS treatment there is one certainty. Once antiretroviral (ARV) treatment begins, drug resistance will inevitably set in amongst a percentage of patients each year, as the virus mutates and adapts - even in the best of medical environments. Those patients that demonstrate resistance to first-line therapies have to switch to second—or even third–line "salvage" therapies, which are considerably more costly to administer and monitor.

While this is a serious problem even for well–financed Western health systems, it is extremely bad news for patients in developing countries where the disease is most prevalent. Unfortunately, HIV drug resistance is being encouraged by the well–meaning but short–sighted policies of multilateral institutions like the WHO, and philanthropic bodies like the Clinton Foundation. In this instance, kindness really can kill.

According to the World Bank, HIV–1 resistance rates to first–line therapies in 2004 ranged from 6 per cent in Brazil, to 15 per cent in France, and 28 per cent in the USA.

The lower rate of resistance in a poorer country like Brazil is no cause for celebration, however. The USA was the first nation to start widespread treatment therapy for AIDS sufferers in 1988, when ARVs first came onto the market. Brazil followed a decade later in 1999. Most of the poorest countries only initiated mass treatment programmes as recently as 2003, under the auspices of the WHO's "3 by 5" programme. So drug resistance rates in less developed countries are almost certain to rise rapidly over the next decade.

Why does drug resistance matter? Newer, second–line HIV therapies are significantly more expensive than older drugs. But this expense is dwarfed by the cost of the extra medical expertise, monitoring and in–patient care that is required to administer newer therapies. As the IMF has warned, the billions of dollars of aid money required to finance salvage therapies could seriously destabilise the economies of poor countries.

Also, for patients with drug–resistant HIV, the chances of maintaining a reasonable quality of life decline rapidly once resistance sets in—particularly in the resource-starved health care systems in much of Africa, where specialised HIV care is much harder to come by.

If drug resistance is such a problem, one would assume that a major goal of international AIDS treatment programmes would be to delay the onset of resistance for as long as possible. sanpost Unfortunately, the various global actors responsible for designing and financing ARV treatment programmes have not taken this threat seriously, and in so doing have jeopardised patient safety on a massive scale.

One of the most negligent bodies has been the WHO, in particular its ill–fated "3 by 5" programme. The goal of this programme was to get 3 million patients on ARV treatment between 2003 and 2005, an insanely challenging target that necessitated an extremely rapid scale—up of treatment in some of the most dysfunctional health systems in the world. Malawi, for instance, has 7,435 AIDS patients per medical doctor in the country.

In order to try and hit its targets, the WHO based its treatment model on so–called "fixed–dose combinations"—cocktails of patented drugs, which, assembled as combinations, could be sold as generics. The WHO reasoned that these would not only be cheap, but would simplify treatment and thereby obviate the need for costly and complicated patient compliance regimes.

The only problem was that these "fixed–dose combinations" were not true generics, which have to be tested for bioequivalence by a stringent regulatory authority like the U.S. FDA. Rather, they were in effect experimental copies of unknown quality, whose effect on patients was impossible to accurately predict. If a copy drug has sub–optimal levels of active ingredient, or is sub–standard in other ways, the patient can undergo clinical failure and suffer from an increased risk of drug resistance.

In 2004, the WHO belatedly recognised the dangers of this approach when it was forced to "de–list" 18 Indian–made copy drugs from its pre–qualification list. Inspections of the Indian factories revealed a lack of adherence to international Good Clinical Research and Laboratory Practice, as well as problems with bioequivalence data. In effect, the safety of millions of AIDS patients in Africa had been put at risk by the use of therapies that were, at best, experimental. Some of these drugs, including two manufactured by Cipla and three by Ranbaxy, were later re–listed after they proved their quality.

The true extent of the damage done by the mass use of untested AIDS drugs may never be fully known. "3 by 5" paid little attention to the monitoring of drug resistance, and there is consequently little data available.

But where scientists are tracking drug resistance, the findings are grim. Since 2002, the Thai government had been basing its AIDS treatment program on GPO–Vir, a triple fixed–dose combination containing stavudine, lamivudine and nevirapine. In late 2006, the interim military government of Thailand issued a compulsory license for Stocrin, a second–line ARV, claiming that it would not be able to afford to treat thousands of patients who had developed resistance to the nevirapine component of GPO–Vir.

Like many of the drugs on the WHO's pre–qualification list, GPO–Vir drug had not been tested for bioequivalence, and neither did its factory meet international Good Manufacturing Practices. Perhaps inevitably, Thai scientists reported in 2004 startling levels of resistance to the various components of GPO–Vir, particularly nevirapine. We can expect similar reports from around the world in years to come.

The global community appears to be sharply divided over how to address HIV drug resistance. The United States seems to be taking a prudent course. Following the WHO's de–listing debacle, in 2004 the FDA offered the WHO free, fast–track bioequivalence testing, and several Indian companies have since stepped up to this plate to prove the quality of their generics. More than 70 per cent of ARVs purchased by the President's Emergency Plan for AIDS Relief (PEPFAR) have been certified by the FDA as true generics, rather than copies of an indeterminate quality.

NGOs, on the other hand, have shrugged their shoulders. The Clinton Foundation continues to procure Indian–manufactured ARVs that have not been properly tested for bioequivalence. Likewise, some 90 per cent of all ARVs recommended by the WHO's pre–qualification programme are copies rather than true generics.

International activist groups have also behaved somewhat irresponsibly. Médecins Sans Frontières (Doctors without Borders) continues to distribute the experimental GPO-Vir in Cambodia and Myanmar, and has vociferously opposed the FDA’s offer of bioequivalence testing, arguing that it would undermine the WHO and delay access to medicines.

Problems with copy drugs are not confined to HIV/AIDS. Only 7 per cent of the anti–malarial drugs financed by the Global Fund for AIDS, Malaria and Tuberculosis have undergone rigorous bioequivalence testing. The emergence of strains of malaria resistant to Artemisinin would be a disastrous setback for the fight against malaria—not least because there is little prospect of a viable alternative treatment coming onto the market in the next few years. This problem is compounded by the recent surge of fake anti–malarials doing the rounds in Africa and Asia: as Roger Bate has argued, official acceptance of copy drugs makes it more difficult to control and regulate these deadly knock–offs.

The implications are clear. If it is to continue recommending particular treatments to member states, the WHO must be more rigorous in its bioequivalence and quality requirements. Likewise, the donor agencies that finance drug procurement should be more discriminating, and demand better data and the highest standards.

We wouldn't give untested therapies to a patient in Europe or the US. And so it is wrong to visit this double standard on patients in Africa, just because they happen to be poor.

Philip Stevens is the Health Programme Director at the International Policy Network and the author of numerous health policy publications, including Fighting the diseases of poverty (2007), Free trade for better health (2005), and The 10/90 Gap and the diseases of poverty (2004). His writings on health policy have appeared in a wide range of international newspapers. Philip has also held research positions at the Adam Smith Institute and Reform in London, and spent several years as a management consultant. He holds degrees from the London School of Economics and Durham University.
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