WHO’s Dubious Bag of HIV Medicines (Unabridged Version)

Los Angeles Times, July 1, 2004

By Sally Satel

The World Health Organization is racing against time to get medication to millions of people infected with HIV/AIDS. The goal of the organization’s “3 by 5 plan” is to treat 3 million people, mostly Africans, by the end of 2005. The plan will surely be a focus of the upcoming International AIDS Conference in Bangkok – an ideal venue for raising questions about whether WHO is implementing the campaign responsibly.

A red flag went up last month when WHO announced that two medications on its list of approved HIV drugs could not be shown to meet quality standards. The drugs were anti-retroviral drugs made by Cipla, an Indian manufacturer whose major business is copying pharmaceuticals invented and patented by other companies, mainly in the United States. The problem? The raw data on the two drugs — lamivudine and a lamivudine-zidovudine combination (called Duovir) – “failed to prove bioequivalence,” in the words of WHO.

Bioequivalence means that the tested drug delivers as much medication to a person’s system as the gold-standard, patented form of the drug. In the case of an anti-retroviral medication for HIV/AIDS, low concentrations in blood and tissues make it harder to keep the virus from multiplying. The more often a virus reproduces itself, the more chances for it to create mutant forms, some of which will no longer respond to medication. Thus, when these mutated forms multiply within an individual, or if they are transmitted to another person, resistant strains spread and the disease becomes harder and harder to contain.

Since the two Cipla-made drugs were approved (“prequalified”) by WHO in 2002 and 2003, respectively, thousands of Africans have been taking them. The lack of proof of bioequivalence was first detected in May and did not become public until June 17 when WHO issued a formal press release.

No one knows exactly how long the suspect drugs have been in use. But we do know that the longer patients are exposed to inadequate doses, the more chance for drug-resistant HIV strains to develop. To what extent has this happened? Who will contact these individuals and tell them to discontinue the medications? And what medications will they now take in place of these two “de-listed” drugs?

How the WHO will handle the bioequivalence problem is not the only question it faces. Some global health experts also worry that the organization is promoting a questionable treatment in the form of a pill called Triomune, also made by Cipla, as its first-line medication in the “3 by 5” initiative. Triomune contains a three standard HIV drug compounds (lamivudine, stavudine, nevirapine), each at a fixed dose and combined together in one pill.

WHO officials emphasize that a combination pill is easier to buy in bulk and distribute. Not to mention the convenience of a single pill taken twice a day. Many Western patients take up to twenty pills over the course of the day, so ease of administration is no small matter. Indeed, compliance is crucial as regular dosing maintains good blood levels, which, in turn, reduce the risk of creating treatment-resistant HIV strains.

But there are potential problems. The WHO does not test drugs, and its criteria for putting medicines on its List of Essential Medicines are unclear. Triomune has not been given approval by the U.S. Food & Drug Administration because Cipla has not submitted it.

Many health experts are rightly skeptical of a one-size-fits-all approach to a complex disease that doctors in the West routinely treat with a flexible armamentarium of drugs, adjusted to each patient. Specific drugs are switched often or their dosage strengths changed depending upon side-effects, progress of the disease itself, and other medical problems the patient suffers.

A doctor’s freedom to custom-tailor a cocktail is essential. For example, if a patient is taking treatment for tuberculosis, the clinician must choose an HIV drug that does not interact with the tuberculosis drug to produce a toxic reaction. Or a patient might have problems with his liver prompting the doctor to avoid using HIV medications that pose their own significant risks to a damaged liver. And then there are side effects, which doctors try to minimize by starting at a low dose and building up gradually; a fixed dose pill makes this impossible.

A 3 in 1 pill dramatically cuts the treatment options for patients because it must obey certain requirements. For one thing, the component drugs need to be chemically compatible so that they can be combined together in a pill. Also, ideally, the pill would contain only components that are safe for a fetus, should a young woman become pregnant. In addition, at least one of the compounds should be able to prevent mother to fetus transmission.

Satisfying these requirements means that a drug called nevirapine must be included as one of the three components. But unfortunately, nevirapine carries substantial risk of liver damage, precluding its use in a sizeable fraction of patients. It can also cause a life-threatening skin condition, which can often be avoided by gradually increasing the dose – something a fixed 3 in I therapy does not permit.

In rural Africa, where sophisticated medical care is lacking, a calculable percentage of patients will become very sick or even die from nevaripine drug itself. Thus, a dilemma: the need to balance drug-related deaths and illness from a Triomune strategy against the people that would go untreated altogether if aid agencies adopted a more expensive but flexible strategy.

But even for patients who can, in theory, use Triomune, serious doubts have been raised by the WHO ruling on the two other Cipla drugs. After all lamivudine, one of those drugs, is an ingredient in Triomune.

A more reasonable policy for the WHO, since it doesn’t do its own testing, is to rely on the FDA and European drug agencies for approvals. As attention turns to the International AIDS Conference next month, the WHO must regain the world’s confidence, not promote uncertain drug therapies.