P. falciparum susceptibility to ACT declining in India
SAN DIEGO — Recent data presented at ICAAC 2015 suggest that the susceptibility of Plasmodium falciparum to artemisinin-based combination therapy is declining on the Indian subcontinent, especially in sicker patients with a high parasite burden.
The reduced susceptibility does not appear to be related to the use of counterfeit drugs or inferior quality of treatment, but possibly a resistant mutation in the parasite itself.
The use of artemisinin-based combination therapy (ACT) has been the mainstay of treatment for severe malaria since 2005, leading to significant reductions in morbidity and mortality, according to Priscilla Rupali, MD, of the department of infectious diseases at Christian Medical College in Vellore, South India. However, “after the widespread use of artemisinin, slow parasite clearance has heralded the decreased susceptibility of parasites” to the treatment, Rupali said during a presentation.
The spread of resistant malaria in India places thousands of lives at risk. In the 1960s, drug-resistant P. falciparum spread in India, and by 1976, up to 6.45 million cases of malaria were recorded by the National Malaria Eradication Programme. A recent study published in The Lancet Infectious Diseases showed that artemisinin resistance to P. falciparum has re-emerged in Myanmar, which is considered a gateway to India. Researchers reported an overall prevalence of resistance exceeding 10% in the north and east of that country.
“Malaria is grossly underestimated in India,” Rupali told Infectious Disease News. “If there is resistance to artemisinin combination therapy, we have no suitable therapeutic options in the immediate pipeline.”
Due to the increasing number of reports of poor clinical response to ACT at their institution, which is located in a low-endemic area, Rupali and colleagues conducted a retrospective chart review of 116 patients infected with P. vivax, P. falciparum and mixed malaria from July 2010 to June 2011. Of 57 patients with evaluable smears, 59.6% had persistent day-3 parasitemia and 33.3% had a fever clearance time of greater than 72 hours. However, according to Rupali, there is a probable inherent referral bias as only sicker patients are referred to a tertiary care center.
Therefore, the researchers conducted a prospective, observational cohort study to more clearly gauge the incidence of treatment failure among their patients and to assess the clinical response and parasitological clearance of P. falciparum in those treated with ACT. Rupali and colleagues correlated pharmacokinetics of artesunate with treatment response, and preserved samples for future analysis to identify genetic markers of resistance. Their study included 54 slide-confirmed cases of P. falciparum and mixed malaria on ACT (85% male). Fifty-one patents aged 15 to 60 years completed follow-up on day 7. Rupali said 16 cases were included in the pharmacokinetic analyses.
Approximately three-quarters (74%) of patients had severe malaria, and more than one-quarter (25.5%) experienced delayed parasite clearance after ACT, Rupali said. In the entire cohort, the median time to parasite clearance was 36 hours (95% CI, 27.08–44.91), and the median time to fever clearance was 24 hours (95% CI, 18.69–29.30). In the group with delayed parasite clearance, the median time to parasite clearance was 72.92 hours, while the median time to fever clearance was 84.6 hours. Results also showed that the group with delayed parasite clearance had prolonged gametocytemia. For example, cases of delayed parasite clearance had a median gametocyte clearance time of 7 days (range, 3-19) compared with 3.5 days (range, 1-14) among those who successfully responded to treatment.
Pharmacokinetic variables — including Cmax, AUC0-240 and clearance — were similar between responders and delayed responders.
Rupali said that because the treatment was dispensed at her hospital, the researchers were able to rule out the possibility that any drug resistance observed in the study was attributable to the use of counterfeit drugs.
She acknowledged that the small sample size was a limitation, and the researches were unable to calculate parasite density and parasite clearance half-lives — a more accurate indicator of treatment failure than day-3 parasitemia rates. The small number of patients included in the pharmacokinetic analyses was another limitation, she said.
“We found that 25% of our patients fulfilled the WHO criteria for suspected partial artemisinin resistance in south India,” Rupali said during her presentation, emphasizing the need for a nationwide study of artemisinin resistance.
Samples collected during the study will be assessed for mutations in the propeller region of the K13 Kelch gene, a known marker for artemisinin resistance in P. falciparum, Rupali said, and plans are underway to determine adequate dosing of artemisinin in the Indian population, especially in sicker patients with high parasite burden. – by John Schoen
Rupali P, et al. Correlation of Artesunate Pharmacokinetics with Delayed Response to Artesunate Combination Therapy (ACT) in P. falciparum Malaria from South India. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.
WHO. Status report on artemisinin resistance. September 2014. http://www.who.int/malaria/publications/atoz/status_rep_artemisinin_resistance_sep2014.pdf. Accessed September 28, 2015.
Disclosure: Rupali reports no relevant financial disclosures.