Malaria Treatment Resistance Might Be Looming in Vietnam

Daniel M. Keller, PhD

July 11, 2012

July 11, 2012 (Bangkok, Thailand) — It is possible that falciparum malaria parasites in southern Vietnam, near the Cambodian border, are developing resistance to the antimalarial drug artemisinin, according to a study presented here at the 15th International Congress on Infectious Diseases.

Tran Tinh Hien, MD, PhD, vice-director of clinical research at the Oxford University Clinical Research Unit Wellcome Trust Major Overseas Programme, staff member at the Hospital for Tropical Diseases in Ho Chi Minh City in Vietnam, and member of the Centre for Tropical Medicine at Churchill Hospital in Oxford, United Kingdom, reported that more than 20 years ago, Vietnam became one of the first countries to begin using artemisinin and its derivatives.

Since then, the country has seen a drop in the incidence of malaria, but it remains a public health challenge. In 2005, the country began using dihydroartemisinin-piperaquine (DHA/PPQ) as first-line treatment for falciparum malaria. Another artemisinin derivative, artesunate, is a semisynthetic water-soluble derivative of DHA.

In eastern Cambodia, which borders Vietnam, parasitologic responses to artesunate-based regimens for uncomplicated falciparum malaria are slower than in the rest of the world, and the rate of treatment failure is higher. "There is population movement between the 2 countries every day, so we conducted a study to clarify whether the resistance of Plasmodium falciparum to artesunate has moved to Vietnam," Dr. Hien told Medscape Medical News.

From August 2010 to May 2011, researchers randomized 166 patients 10 years and older with uncomplicated falciparum malaria to artesunate 2 mg/kg or 4 mg/kg daily for 3 days, followed by a full 3-day course of DHA/PPQ (40 mg/320 mg twice daily on day 1 and once daily on days 2 and 3), or to full-course DHA/PPQ alone.

The researchers monitored clinical and parasitologic responses weekly for 6 weeks. They used a polymerase chain reaction (PCR)-based analysis of parasite DNA to distinguish recrudescence related to treatment failure from reinfection.

Early Warning Sign for Treatment Resistance

"We haven't found any real resistance, but the parasite clearance is longer than usual," Dr. Hien reported. However, there was no statistically significant difference among the 3 treatment regimens in the rate of clearance of P falciparum parasites from the blood.

In Vivo Effectiveness of the Treatment Regimens

Measures of Effectiveness Artesunate 2 mg/kg + DHA/PPQ Artesunate 4 mg/kg + DHA/PPQ DHA/PPQ P Value
Median Parasite Clearance Half-Life (h) 3.54 2.72 2.98 .19
Median Parasite Reduction Ratio at 24 h 48 212 113 .02
Proportion of Patients With Parasite Clearance >72 h, % 27 27 22

The time to clear the parasites is a sign of creeping resistance, Dr. Hien said. In all 3 groups, approximately one quarter of the patients showed a parasite clearance time exceeding 72 hours. "About 5 years ago, the positivity of the smear [at 72 hours] was less than 5%; now it has increased to above 25%," he explained.

The median parasite reduction ratios at 24 hours were greater with higher-dose artesunate and DHA/PPQ alone than with lower-dose artesunate.

In the lower-dose group (n = 55), there were 2 (4%) early treatment failures and 1 (2%) late clinical failure; in the other 2 groups, there were no treatment failures.

World Health Organization (WHO)-defined PCR-corrected adequate clinical and parasitologic responses in the 2 mg/kg, 4 mg/kg, and DHA/PPQ groups were 94%, 100%, and 100%, respectively.

The researchers found that a white blood cell count below 5000/μL was the most common adverse effect, but counts recovered after 2 weeks.

They concluded that P falciparum parasite clearance was more rapid in southern Vietnam compared with previous data for Cambodia, but slower compared with historic data for Vietnam.

In Cambodia, many papers published report that resistance is higher now than it was before 2009, Dr. Hien noted.

The researchers concluded that, on the basis of WHO criteria for early and late treatment failures, therapeutic response to DHA/PPQ is currently satisfactory in Vietnam.

"In the end, patient outcome is still okay, but I am starting to see some alarming signs," Dr. Hien warned. It is possible that in 4 or 5 years, adequate clinical and parasitologic responses will decrease. "We don't know," he said.

He said the worry now is that resistance to artemisinin-based therapy might be spreading to other countries — at first to the countries surrounding Cambodia ( Vietnam, Laos, and Thailand). "At least 2 places — western Cambodia and Thailand — already confer what they call the tolerance to artesunate of P falciparum." Dr. Hien said, noting that "we have started to monitor the response of P falciparum in Vietnam." For example, we follow 4 or 5 sentinel signs in vivo to see whether response is good or not good.

If the parasites become resistant to artesunate, clinicians will have to decide which drugs to use. Chansuda Wongsrichanalai, MD, DPH, an independent consultant in Bangkok, Thailand, who formerly worked for the US Agency for International Development (as part of the Armed Forces Institute of Medical Sciences in Bangkok and the Naval Medical Research Unit 2 in Indonesia and Cambodia), told Medscape Medical News that it is possible that a new totally synthetic compound, arterolane, recently developed by Ranbaxy in India, will work. It is used in combination with piperaquine. "But it hasn't been tested on the Thai–Cambodian border, so we don't know if a strain that is resistant to the usual artemisinin would be killed," she said.

In southern Vietnam, the effectiveness of artemisinin is not bad, but it is not as good as it was years ago, Dr. Wongsrichanalai noted. "For the whole subregion, it's a worrying sign because we have had delayed clearance with artemisinin on the Myanmar–Thailand border since 2009. WHO is...trying to confirm what's happening, but it's hard to...because of the political situation in Myanmar."

She said that Myanmar imposes some travel restrictions on its citizens, but the economy in several Thai provinces depends heavily on workers from Myanmar. Certainly, "several provinces will have to shut down everything if you close the gates," she said. "There are millions of [these migrants] in Thailand right now, and they travel as far as the Thai–Cambodian border, which is the hotspot for artemisinin resistance. We are afraid that they will...carry the resistant strain back to Myanmar and then spread it west, just like chloroquine resistance was spread 30 years ago."

There was no commercial funding for the study. Dr. Hien and Dr. Wongsrichanalai have disclosed no relevant financial relationships.

15th International Congress on Infectious Diseases (ICID): Abstract 42.020. Presented June 14, 2012.


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