Date Published: May 16, 2017
Publisher: Public Library of Science
Author(s): Tesfay Abreha, Jimee Hwang, Kamala Thriemer, Yehualashet Tadesse, Samuel Girma, Zenebe Melaku, Ashenafi Assef, Moges Kassa, Mark D. Chatfield, Keren Z. Landman, Stella M. Chenet, Naomi W. Lucchi, Venkatachalam Udhayakumar, Zhiyong Zhou, Ya Ping Shi, S. Patrick Kachur, Daddi Jima, Amha Kebede, Hiwot Solomon, Addis Mekasha, Bereket Hailegiorgis Alemayehu, Joseph L. Malone, Gunewardena Dissanayake, Hiwot Teka, Sarah Auburn, Lorenz von Seidlein, Ric N. Price, Clara Menendez
Abstract: BackgroundRecent efforts in malaria control have resulted in great gains in reducing the burden of Plasmodium falciparum, but P. vivax has been more refractory. Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia.Methods and findingsPatients with normal glucose-6-phosphate dehydrogenase status with symptomatic P. vivax mono-infection were enrolled and randomly assigned to receive either chloroquine (CQ) or artemether-lumefantrine (AL), alone or in combination with 14 d of semi-supervised primaquine (PQ) (3.5 mg/kg total). A total of 398 patients (n = 104 in the CQ arm, n = 100 in the AL arm, n = 102 in the CQ+PQ arm, and n = 92 in the AL+PQ arm) were followed for 1 y, and recurrent episodes were treated with the same treatment allocated at enrolment. The primary endpoints were the risk of P. vivax recurrence at day 28 and at day 42.The risk of recurrent P. vivax infection at day 28 was 4.0% (95% CI 1.5%–10.4%) after CQ treatment and 0% (95% CI 0%–4.0%) after CQ+PQ. The corresponding risks were 12.0% (95% CI 6.8%–20.6%) following AL alone and 2.3% (95% CI 0.6%–9.0%) following AL+PQ. On day 42, the risk was 18.7% (95% CI 12.2%–28.0%) after CQ, 1.2% (95% CI 0.2%–8.0%) after CQ+PQ, 29.9% (95% CI 21.6%–40.5%) after AL, and 5.9% (95% CI 2.4%–13.5%) after AL+PQ (overall p < 0.001). In those not prescribed PQ, the risk of recurrence by day 42 appeared greater following AL treatment than CQ treatment (HR = 1.8 [95% CI 1.0–3.2]; p = 0.059). At the end of follow-up, the incidence rate of P. vivax was 2.2 episodes/person-year for patients treated with CQ compared to 0.4 for patients treated with CQ+PQ (rate ratio: 5.1 [95% CI 2.9–9.1]; p < 0.001) and 2.3 episodes/person-year for AL compared to 0.5 for AL+PQ (rate ratio: 6.4 [95% CI 3.6–11.3]; p < 0.001). There was no difference in the occurrence of adverse events between treatment arms.The main limitations of the study were the early termination of the trial and the omission of haemoglobin measurement after day 42, resulting in an inability to estimate the cumulative risk of anaemia.ConclusionsDespite evidence of CQ-resistant P. vivax, the risk of recurrence in this study was greater following treatment with AL unless it was combined with a supervised course of PQ. PQ combined with either CQ or AL was well tolerated and reduced recurrence of vivax malaria by 5-fold at 1 y.Trial registrationClinicalTrials.gov NCT01680406
Partial Text: Almost 3 billion people live at risk of Plasmodium vivax infection [1,2], with over 100 million clinical malaria cases estimated to occur each year . The greatest burden of P. vivax malaria is in the Asia-Pacific region and South America, whereas on the African continent, P. vivax infection is limited mostly to the Horn of Africa. Recent intensification of malaria control efforts has reduced the global burden of P. falciparum malaria, but P. vivax has been more refractory. Vivax malaria is more difficult to cure than falciparum malaria, due to its ability to form dormant liver stages (hypnozoites) that reactivate periodically, causing relapsing infections and onward transmission. Chloroquine (CQ) remains the mainstay of treatment for vivax malaria in most endemic countries, but drug resistance has emerged in South-East Asia and is spreading . Relapsing and increasingly frequent recrudescent infections cause repeated symptomatic illnesses, worsening the risk of anaemia and severe and fatal disease [5,6].
This study highlights that the combination of PQ with either CQ or AL reduced the risk of early recurrence (within 42 d) of P. vivax by up to 3-fold, and decreased the risk of recurrence over 1 y by 2- to 3-fold, compared to CQ or AL alone. PQ (3.5 mg/kg over 14 d) was well tolerated, without significant adverse effects. Recent clinical trials have highlighted the declining efficacy of CQ against P. vivax in Ethiopia [18–20], with the risk of recurrence at day 28 ranging from 14%  to 22% . Our study provides evidence of low-grade CQ resistance [4,22], with 3.8% of patients having recurrence by day 28 in the presence of adequate CQ blood concentration (>100 nM). However, despite CQ’s compromised efficacy, the risk of recurrence was almost 2-fold greater in patients treated with AL alone compared to those treated with CQ alone, although this difference did not reach statistical significance (p = 0.059). In equatorial regions endemic for P. vivax, including Ethiopia, the risk of P. vivax relapse is generally high, with the first recurrence occurring about 21 d following the initial treatment . Lumefantrine has an elimination half-life of 3–6 d, and, by 16 d, drug concentrations have fallen well below the minimum inhibitory concentration for the parasite and thus are no longer sufficient to prevent relapsing infections. Conversely, the slower elimination of CQ affords prolonged post-treatment prophylaxis, capable of suppressing early relapses . By day 42, both CQ and lumefantrine levels are expected to be below the minimum inhibitory concentration, and, hence, in the absence of PQ, it is not surprising that there was no difference in the incidence of recurrent infections beyond that time.