How fast do drug-resistant strains spread?

Any living thing under attack will try to defend itself. In the case of malaria parasites, with their tremendously huge populations and short generation times—inside the bodies of mosquitoes and their hosts, malaria parasites multiply their numbers in a matter of days—defensive tactics can emerge rapidly.

Inside a single infected person, the number of plasmodium falciparum parasites can multiply to 100,000,000,000, some portion of which will inevitably sport genetic mutations. Sometimes only one or two mutations are required to circumvent the action of a whole class of antimalarial drugs. It may not happen right away, but when it happens, it spreads fast.

Studies of the plasmodium falciparum genome have revealed that chloroquine-resistant parasites emerged only rarely in the global population of parasites, but once they did, they spread across the globe.

In 1960, two geologists who had been working for an oil company in Colombia staggered into a Dallas hospital. They were suffering falciparum malaria. But chloroquine, the king of anti-malarial drugs, failed to cure them. Not long after, doctors in Bethesda treated a patient who contracted falciparum in Thailand. Chloroquine didn’t work for this patient, either. Between 1961 and 1962, parasites resistant to the antimalarial pyrimethamine in table salt emerged in the Netherlands, Brazil, and Cambodia. Then, Plasmodium falciparum resistant to chloroquine, distributed in table salt, emerged in Colombia, Brazil, Venezuela and Thailand.

These parasites, commented CDC’s Peter Bloland, “eat chloroquine for lunch.”

By 1965, chloroquine-resistant Plasmodium had infected over 1,800 U.S. soldiers fighting in Vietnam. More hospital beds were filled with malaria patients than with those wounded by the enemy, a sadly reminiscent scene reported by the New York Times. At first quinine worked to quell the chloroquine-resistant parasites, but soon parasites resistant to all known antimalarials had emerged. The drugs would in some cases reduce fever for a while, but they’d no longer kill the parasites. That meant that patients might still use the meds but the parasite would continue infecting others, unhindered. During the Vietnam war, the U.S. lost twelve soldiers to drug-resistant malaria.

Parasites resistant to mefloquine emerged a year after its commercial launch by Hoffman La Roche.

New antimalarial drugs such as sulphadoxin-pyrimethamine, also known as Fansidar introduced in 1973, failed to contain the parasite. Only a few genetic mutations were necessary for Plasmodium to circumvent Fansidar. Many more were required to render the parasite resistant to chloroquine. Fansidar-resistant strains emerged and began to spread by 1978.

By the end of the 1980s, the parasite had emerged, victorious. Malaria had evolved strains resistant to all known drugs.

In 1981, Chinese scientists derived the active ingredient artemether from an extract of sweet wormwood tree—artemisinin—and had proved its remarkable efficacy against Plasmodium, even chloroquine-resistant strains. Artemisinin cured falciparum faster and with less toxicity than quinine or chloroquine. Symptomatic relief required just 2 days worth of drug, but to effect a cure—killing all the parasites, including the gametocyte forms of the parasite that spread the disease—patients would have to remain on drug therapy for 7 days.

Chinese and Vietnamese drug companies quickly launched a plethora of artemisinin drugs. By 1990, China’s caseload of malaria dropped from 2 million in 1980 to just 90,000. Western drug companies muscled in to the hot new market. By the early 1990s, Aventis was selling its artemisinin drug “Paluther” in Africa. Belgian company Arenco launched a similar artemisinin drug “Artennam.” Across Asia and Africa, against a backdrop of boarded-up government malaria clinics, malaria patients took their health into their own hands. Sweet wormwood soon became their drug of choice.

Chinese scientists, cognizant that they had developed the only effective cure for drug-resistant malaria, prudently decided to try to protect the drug from the parasite’s mutating wiles. They combined artemether with another anti-malarial called lumefantrine. They engineered a way to compound the two drugs together, in the same pill so that patients couldn’t decide to take the favored artemether and ditch the lumefantrine. Simulataneously bombarded with both drugs, the parasite would be much less likely to develop resistance to either.

In 1994, the Chinese team sold the rights to artemether-lufantrine to drug giant Novartis. Novartis didn’t launch the drug until 1999, but “Riamet”, at $44 per course, was aimed primarily at Western travelers, not malarious locals. Stand-alone artemisinin remained all the rage across Africa. Belgian company Dafra alone earned $13 million a year selling stand-alone artemisinin drugs in Africa. One survey of artemisinin products in African markets found that many were package with instructions to take the drug for five days, enough to make the patient feel well, but not enough to kill the parasite.

By 2001, the WHO had revised its guidelines on antimalarial drug therapy, recommending that artemisinin combination drugs should be the first-line drug against malaria for all cases, everywhere. Novartis agreed to sell Riamet to the WHO for $2 a course (the cheaper version is called Coartem).

But even at that price, Coartem was 10 to 20 times more expensive than chloroquine or Fansidar, and the international donors who foot the bill for malaria treatments in Africa and Asia balked. People from USAID and CDC considered the combo drug too expensive, scarce, and potentially confusing to patients. In a 2003 malaria epidemic in Ethiopia, UNICEF refused to pay for and use artemisinin combination drugs.

African and malaria aid physicians protested, but without USAID or other funders’ support, there was no way developing countries’ health ministries could weather a 10-fold increase in malaria drug prices. And so, in countries like Senegal, health ministers continue to tell their clinicians to prescribe the nearly useless chloroquine for malaria.

In the financial and regulatory vacuum, an underground market in artemisinin drugs thrived. Sales of Aventis’ and Rhone-Poulenc’s artemisinin drugs on the private market flourished. Hopeful Brazilians and Guyanese lured by the prospect of gold in the tiny chunk of jungle-covered coast that is French Guiana slashed through the rainforest. A stream of illegally imported artemisinin staved off the malaria that plagued them.

Strains of plasmodium resistant to artemisinin combination drugs were recorded in DATETK.

Countering drug resistant malaria requires a heavily funded, ongoing effort to continually develop new malaria drugs. With the buying power of malaria patients minimal ($200 million a year, compared to the annual billions arthritis or hypertension patients will spend on drugs) private drug companies devote little or no R&D to malaria. Between 1975 and 1999, only 4 of nearly 1,400 new drugs were antimalarials, and even these four were developed by publicly funded researchers. In the vacuum, NGOs such as the Medicines for Malaria Venture have been formed to encourage new drug development for malaria. As of 2004, global funds to develop new malaria drugs ran to about $50 million a year, less than one-sixteenth the amount drug companies claim to spend on each new drug they launch.

It is not impossible to stamp out drug-resistant strains. In Malawi, health authorities were able to fully stanch chloroquine use in 1993. Today, chloroquine works, once more, against malaria strains present in Malawi. Managing drug use, however, requires that governments adequately regulate and oversee physicians, pharmacists, and most importantly, drug companies. In many countries where malaria is rife, government regulation and oversight is poor at best.

For more:

Kenneth J Arrow et al, eds., Saving Lives, Buying Time: Economics of malaria drugs in an age of resistance (Washington, DC: National Academies Press, 2004

Carol Hopkins Sibley and Pascal Ringwald, “A database of antimalarial drug resistance,” Malaria Journal, June 15, 2006 http://www.malariajournal.com/content/5/1/48/abstract

International Network for the Rational Use of Drugs
http://www.inrud.org/

Medicines for Malaria Venture
http://www.mmv.org/

World Antimalarial Drug Resistance Network launched
http://www.medicalnewstoday.com/articles/81701.php