In the Journals

Combination artemisinin treatment failures in Cambodia suggest growing resistance

The combination malaria treatment dihydroartemisinin-piperaquine appears to be failing in certain regions of Cambodia, driving the need for further research exploring and circumventing this emerging resistance, according to a recent study published in The Lancet Infectious Diseases.

Dihydroartemisinin-piperaquine, one of the few artemisinin combination therapies still effective against multidrug-resistant [Plasmodium falciparum] in Southeast Asia, was adopted as the first-line antimalarial treatment in Cambodia in 2008,” the researchers wrote. “Several earlier studies documented the excellent safety and tolerability … however, the rapid spread of artemisinin resistance in Cambodia and throughout mainland Southeast Asia threatens the efficacy of dihydroartemisinin-piperaquine and all other artemisinin combination therapies.”

Recrudescence, time to clearance greater in provinces with emerging resistance

To investigate the impact of resistance in this region, researchers enrolled patients aged 2 to 65 years with acute, uncomplicated P. falciparum malaria in three Cambodian provinces. Participants were eligible if they demonstrated a fever within the previous 24 hours, parasitic density no greater than 200,000 per μL and did not receive antimalarial treatment within the previous week. Patients received a standard 3-day treatment of dihydroartemisinin-piperaquine. Parasite density was checked periodically in the hospital until parasitemia clearance, and then weekly alongside body temperature and illness symptoms until day 63. The primary study outcome was P. falciparum recrudescence, and secondary outcomes included piperaquine plasma concentrations, parasite clearance half-life, the proportion of patients with parasite clearance half-lives greater than 5 hours, and the proportion of patients with parasitemia at 72 hours.

Researchers enrolled 241 patients from Sept. 4, 2012 to Dec. 31, 2013, 212 of whom were followed up to the full 63 days. The median age of the patients (76% male) was 24 years. The median parasite density was 12,249 cells per μL, and did not differ between sites.

The researchers reported the overall proportion of patients with parasite recrudescence to be 26%, with recurrent infections occurring most often in the Pursat providence (46%), where artemisinin resistance is well-established, and least often in the Ratanakiri providence (2%) where resistance is rare. The average time to recurrence and parasite density did not differ between sites. Treatment efficacy with and without PCR correction was greatest in Ratanakiri, while piperaquine concentrations at 7 days were higher in the other two providences. Parasite clearance half-life, time to 90% clearance, the proportion of patients with half-lives longer than 5 hours or detectable parasitemia at 72 hours, and the presence of kelch13 mutations — a known marker for resistance — were all greatest in Pursat.

These results highlight the link between artemisinin resistance emergence and worsened patient outcomes, and reinforce the need to seek alternative treatment strategies among affected areas, the researchers wrote.

“Improvements in the treatment of P. falciparum malaria with real-time drug resistance data, identification and treatment of asymptomatic parasite carriers through community treatment campaigns and prevention of gametocyte transmission to mosquitoes with single low-dose primaquine are now needed more than ever if malaria elimination is to succeed in Southeast Asia,” the researchers wrote.

Resistant P. falciparum threatens Southeast Asia, India

The spread of resistant P. falciparum in the regions surrounding Cambodia has been well-documented over the past few years.

From May 2011 to April 2013, Elizabeth Ashley, MBBS, PhD, the TRAC study lead scientist and a clinical researcher at the Mahidol Oxford Tropical Medicine Research Unit, and colleagues analyzed blood samples from 1,241 adults and children in seven Asian and three African countries. After receiving artesunate for 3 days followed by a 3-day course of artemisinin-based combination therapy, the researchers evaluated parasite counts and clearance half-lives among the patients.

They found median parasite clearance half-lives ranging from 1.8 hours in the Democratic Republic of the Congo to 7 hours at the Thailand-Cambodia border. Slow-clearing infections were associated with the presence of kelch13 mutations, which was detected from southern Vietnam up to central Myanmar. Those with slow parasite clearance also had higher incidence of pre- and posttreatment gametocytemia, and thus more transmission potential.

“Front-line artemisinin combination treatments are still very effective at curing the majority of patients,” Ashley said in a press release. “But we need to be vigilant as cure rates have fallen in areas where artemisinin resistance is established. Action is needed to prevent the spread of resistance from Myanmar into neighboring Bangladesh and India.”

This call was taken up again in early 2015, when researchers examined parasite samples collected at 55 malaria treatment centers across Myanmar and border regions in Thailand and Bangladesh from 2013 to 2014 for kelch13 mutations. Nearly two-fifths of the 940 samples obtained carried the mutation, with resistance prevalence in a region of Myanmar only 25 kilometers from the Indian border reaching as high as 47%.

In light of these findings, the researchers warned that spread of the mutation into India and other regions would place thousands of lives at risk and jeopardize global control of the disease.

“The pace at which the geographical extent of artemisinin resistance is spreading is faster than the rate at which control and elimination measures are being developed and instituted, or new drugs being introduced,” they wrote. “A vigorous international effort to contain this enormous threat is needed.” – by Dave Muoio

References:

Amaratunga C, et al. Lancet Infect Dis. 2016;doi:10.1016/S1473-3099(15)00487-9.
Ashley E, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1314981.
Tun KM, et al. Lancet Infect Dis. 2015;doi:10.1016/S1473-3099(15)70032-0.

Disclosure: The researchers report no relevant financial disclosures.

The combination malaria treatment dihydroartemisinin-piperaquine appears to be failing in certain regions of Cambodia, driving the need for further research exploring and circumventing this emerging resistance, according to a recent study published in The Lancet Infectious Diseases.

Dihydroartemisinin-piperaquine, one of the few artemisinin combination therapies still effective against multidrug-resistant [Plasmodium falciparum] in Southeast Asia, was adopted as the first-line antimalarial treatment in Cambodia in 2008,” the researchers wrote. “Several earlier studies documented the excellent safety and tolerability … however, the rapid spread of artemisinin resistance in Cambodia and throughout mainland Southeast Asia threatens the efficacy of dihydroartemisinin-piperaquine and all other artemisinin combination therapies.”

Recrudescence, time to clearance greater in provinces with emerging resistance

To investigate the impact of resistance in this region, researchers enrolled patients aged 2 to 65 years with acute, uncomplicated P. falciparum malaria in three Cambodian provinces. Participants were eligible if they demonstrated a fever within the previous 24 hours, parasitic density no greater than 200,000 per μL and did not receive antimalarial treatment within the previous week. Patients received a standard 3-day treatment of dihydroartemisinin-piperaquine. Parasite density was checked periodically in the hospital until parasitemia clearance, and then weekly alongside body temperature and illness symptoms until day 63. The primary study outcome was P. falciparum recrudescence, and secondary outcomes included piperaquine plasma concentrations, parasite clearance half-life, the proportion of patients with parasite clearance half-lives greater than 5 hours, and the proportion of patients with parasitemia at 72 hours.

Researchers enrolled 241 patients from Sept. 4, 2012 to Dec. 31, 2013, 212 of whom were followed up to the full 63 days. The median age of the patients (76% male) was 24 years. The median parasite density was 12,249 cells per μL, and did not differ between sites.

The researchers reported the overall proportion of patients with parasite recrudescence to be 26%, with recurrent infections occurring most often in the Pursat providence (46%), where artemisinin resistance is well-established, and least often in the Ratanakiri providence (2%) where resistance is rare. The average time to recurrence and parasite density did not differ between sites. Treatment efficacy with and without PCR correction was greatest in Ratanakiri, while piperaquine concentrations at 7 days were higher in the other two providences. Parasite clearance half-life, time to 90% clearance, the proportion of patients with half-lives longer than 5 hours or detectable parasitemia at 72 hours, and the presence of kelch13 mutations — a known marker for resistance — were all greatest in Pursat.

These results highlight the link between artemisinin resistance emergence and worsened patient outcomes, and reinforce the need to seek alternative treatment strategies among affected areas, the researchers wrote.

“Improvements in the treatment of P. falciparum malaria with real-time drug resistance data, identification and treatment of asymptomatic parasite carriers through community treatment campaigns and prevention of gametocyte transmission to mosquitoes with single low-dose primaquine are now needed more than ever if malaria elimination is to succeed in Southeast Asia,” the researchers wrote.

Resistant P. falciparum threatens Southeast Asia, India

The spread of resistant P. falciparum in the regions surrounding Cambodia has been well-documented over the past few years.

From May 2011 to April 2013, Elizabeth Ashley, MBBS, PhD, the TRAC study lead scientist and a clinical researcher at the Mahidol Oxford Tropical Medicine Research Unit, and colleagues analyzed blood samples from 1,241 adults and children in seven Asian and three African countries. After receiving artesunate for 3 days followed by a 3-day course of artemisinin-based combination therapy, the researchers evaluated parasite counts and clearance half-lives among the patients.

They found median parasite clearance half-lives ranging from 1.8 hours in the Democratic Republic of the Congo to 7 hours at the Thailand-Cambodia border. Slow-clearing infections were associated with the presence of kelch13 mutations, which was detected from southern Vietnam up to central Myanmar. Those with slow parasite clearance also had higher incidence of pre- and posttreatment gametocytemia, and thus more transmission potential.

“Front-line artemisinin combination treatments are still very effective at curing the majority of patients,” Ashley said in a press release. “But we need to be vigilant as cure rates have fallen in areas where artemisinin resistance is established. Action is needed to prevent the spread of resistance from Myanmar into neighboring Bangladesh and India.”

This call was taken up again in early 2015, when researchers examined parasite samples collected at 55 malaria treatment centers across Myanmar and border regions in Thailand and Bangladesh from 2013 to 2014 for kelch13 mutations. Nearly two-fifths of the 940 samples obtained carried the mutation, with resistance prevalence in a region of Myanmar only 25 kilometers from the Indian border reaching as high as 47%.

In light of these findings, the researchers warned that spread of the mutation into India and other regions would place thousands of lives at risk and jeopardize global control of the disease.

“The pace at which the geographical extent of artemisinin resistance is spreading is faster than the rate at which control and elimination measures are being developed and instituted, or new drugs being introduced,” they wrote. “A vigorous international effort to contain this enormous threat is needed.” – by Dave Muoio

References:

Amaratunga C, et al. Lancet Infect Dis. 2016;doi:10.1016/S1473-3099(15)00487-9.
Ashley E, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1314981.
Tun KM, et al. Lancet Infect Dis. 2015;doi:10.1016/S1473-3099(15)70032-0.

Disclosure: The researchers report no relevant financial disclosures.