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The World Health Organization (WHO) initiated a scale-up on global AIDS treatment in December 2003. At the time, it announced its goal to have 3 million patients under antiretroviral (ARV) therapy by the end of 2005 (so-called “3 x 5” plan). 

It now reports that almost 1 million patients are receiving treatment. In other words, WHO will fall significantly short of its stated goal. But as bad as this tragedy is, an even larger tragedy looms in the distance, and it is a direct result of the WHO’s hasty and ill-conceived scale-up effort.

Dr. Richard Feachem, executive director of the Global Fund for HIV/AIDS, TB and Malaria, was quoted in the Financial Times of August 9 as saying: “Scale-up brings the world to a phase of long-term very substantial morally binding commitments”.  By this he meant that the world “will have to live with millions of people who will stay on antiretrovirals for the rest of their life. To turn off funding would lead to their death in a few weeks or months”.

Neither Feachem nor officials at WHO, however, have offered to discuss publicly the consequences of scale-up, nor the financial implications of “morally binding commitments”. Nor have they focused public attention on an emerging economic pandemic being set in train by drug resistance in the treatment of AIDS patients. To understand why this is so, it helps to go back to late 2003 and early 2004 and examine some of the steps that WHO and their compatriots took in the effort to meet this arbitrary and self-imposed goal.

On December 1, 2003 WHO announced its 3 x 5 plan. At this time, there were less than 200,000 on such treatments in the developing world. In order to meet this rapid scale-up, WHO approved the use of a triple dose combination ARV called Triomune — consisting of lamivudine, stavudine and nevirapine in one single tablet — made by Indian drug companies. It was thought that a combination copy drug would help with patient adherence, a fundamental component of any drug therapy. And, to improve scale-up rates, WHO recommended that basic diagnostic tests be set aside, such as CD 4 cell counts, as they were too expensive in resource-limited settings. Moreover, in October 2003, the Indian companies manufacturing this drug offered it to the William J. Clinton Foundation at $140 per person per year. WHO found this proposal to be attractive and material to its projections to cover 3 million AIDS patients by 2005.

However, this drug had never been subjected to any independently validated clinical trial, nor could it be sold in Australia, the EU, the US, Canada, New Zealand or Japan. In fact, it was never approved by an Indian regulatory authority. Instead it was licensed as a ‘formulation’ by the Drugs Controller General India. Of the conditions listed for its use, one stipulated that “no reference in the advertisement or medical literature is made that the Government has approved the drug”. The two year license was issued on 26 July 2001 and had expired by the time WHO pre-qualified this drug in December 2003. Thereafter, the central legal authority within India shifted to the State of Maharasthra.  Its standards for exported drugs are unknown — although they have been pre-qualified by WHO. 

WHO uses this combination drug as the backbone of its 3 by 5 program even after its production license from India’s central authority had expired. The standards of the State authorities on quality for exported products are unknown. Nor has WHO offered to define the differences between those standards of the central authority vs. the State authorities. There is no record of any substantial sales of this drug via the Clinton Foundation at $140.       

In January 2005, representatives from Indian pharmaceutical producers such as Cipla met in Mumbai with the Community Advisory Board, a group composed of non-governmental organizations. In response to a question inquiring if any countries had received the Clinton discounted price, Cipla’s President responded: “We were told that seven countries were in partnership with Clinton for supplies, and that the total demand would be 2 million patients in the next two years. On that basis we arrived at a price of $140 per patient per year for Triomune. But that was a conditional price. They [Clinton’s staff] announced the price but not the conditions … they are nice people at the Clinton Foundation, but I don’t know how effective they are as an NGO because no business has developed from them”.

Resistance — and Costs — Are Rising

Two recent studies should have set off alarm bells at WHO headquarters and the Global Fund. On July 15, during the 10th National AIDS Seminar in Bangkok, scientists from the faculty of medicine at Ramathibodi Hospital in the Thai capital announced that the rate of drug resistance from antiretroviral copy drugs manufactured by the Government Pharmaceutical Organization (GPO)  have led to dramatic increases in drug resistance and it is expected to worsen. The GPO drug is a triple dose combination consisting of lamivudine, stavudine and nevirapine. The hospital reported the following rates of drug resistance: “lamivudine, 49 percent; stavudine, 39.6 percent; and, nevirapine at 58 percent”.

Thai authorities estimated that while the price of the GPO triple dose drug is $24 per person per month, drug resistance will force patients onto second line therapies in which the price rises to $239 per month, almost a 10 fold increase. Unfortunately, this increase only covers the price of drugs. The costs of medical care treatment, such as by healthcare specialists, in-patient care, etc., have not been factored in. They can be at least three times to four times the product price.

The second study appeared in the August edition of The British Medical Journal. It reported that “resistance to antiviral drugs is climbing and evidence from research that followed 4500 British patients infected with HIV indicates that after two years of standard treatment with a combination of different classes of antiretroviral drugs 10% of people become drug resistant to at least one drug. Six years after starting treatment, 27% are resistant to at least one of their drugs“.

Why should these announcements ring an alarm bell? In the first instance, the therapeutic backbone of WHO’s 3 by 5 program is the use of this same triple dose drug formulation. Although it is pre-qualified by WHO for sale to UN agencies, WHO’s endorsement is offset by this Disclaimer:

“Inclusion in the list does not constitute an endorsement, or warranty of the fitness, of any product for a particular purpose, including in regard of its safety and/or efficacy in the treatment of HIV/AIDS”.

In the second instance, drug resistance is occurring in a developed country with excellent medical care services, highly skilled personnel, and the use of ARVs that have been approved by a stringent regulatory authority.

In other words, drug resistance in AIDS treatment is a fact of life in all clinical settings. What is unknown is its rate of progression when high quality drugs are used vs. substandard drugs.  

In July 2004, The Lancet published an article on the use of the Indian triple dose combination in Cameroon.  The authors pointed out that “there are no clinical trials assessing the effectiveness, safety, and quality of fixed dose combination drugs in resource-limited settings”. Clinical trials are the basis for drug approvals by stringent regulatory authorities. They prove whether a drug does what it is supposed to do without producing adverse side effects to patients. Without them, no drugs can be approved for patient use by developed countries.

Exacerbating the Epidemic?

What might explain the increased drug resistance with triple dose combination ARVs relative to single or dual dose ARVs? Perhaps WHO ignored the dangers of rapid scale-up usin

g untested copy ARVs — instead of true generics — in the absence of basic diagnostic testing.

After all, lesser treatment standards can make a difference to patients’ outcome. The two co-discoverers of the AIDS virus, Drs. Robert Gallo and Luc Montagnier have pointed out that, “if compliance and careful follow-up of patients is not achieved, we will see a dramatic increase in multi-drug-resistant HIV mutants whose further spread will only exacerbate the epidemic”.

Is there a difference between the copy ARVs being promoted by WHO and true generics?

Dr. Terrence Blaschke, professor of medicine and molecular pharmacology at Stanford Medical School published this comment in the Financial Times of September 2003: if a copy drug product is used rather than a generic, then there “is the risk of sub-optimal therapy which can accelerate the emergence of drug-resistance HIV”. 

By failing to assign a proper value to the consequences of initiating wide-scale treatment without understanding the clinical implications of drug resistance, policy-makers drastically underestimate the societal costs involved by the sequential increases in the number of chronically sick people. Their care and maintenance will ultimately prove unsustainable for both donors and affected governments alike, producing in the end an economic pandemic.  

The one international organization that the world should be able to depend upon for surveillance of ARV drug resistance — just as it does for SARS and avian flu — is WHO. But though it continues to promote the use of untested copy drugs from India,  in addition to rapid scale-up, it remains silent on the fatal outcome of these policies: increased drug resistance and “morally binding commitments”.

 Jeremiah Norris is a senior fellow at the Hudson Institute, a non-profit public policy research organization based in Washington, D. C. He was Volunteer with the Peace Corps, and a staff member of Project HOPE, USAID, and Harvard Medical International.
[By Jeremiah Norris,  Published 09/16/2005,  TCS]