Randomized controlled trials of 5- and 14-days primaquine therapy against relapses of vivax malaria in an Afghan refugee settlement in Pakistan. Randomized trial of 3-dose regimens of tafenoquine (WR238605) versus low-dose primaquine for preventing Plasmodium vivax malaria relapse. Blood stage antimalarial efficacy of primaquine in Plasmodium vivax malaria. In-vivo sensitivity of Plasmodium vivax isolates from Rond nia (western Amazon region, Brazil) to regimens including chloroquine and primaquine. Radical curative efficacy of five-day regimen of primaquine for treatment of Plasmodium vivax malaria in India. Clinical efficacy of chloroquine versus artemether-lumefantrine for Plasmodium vivax treatment in Thailand. A double-blind, randomized study of azithromycin compared to chloroquine for the treatment of Plasmodium vivax malaria in India. Efficacy of a 14-day primaquine regimen in preventing relapses in patients with Plasmodium vivax malaria in Mumbai, India. Efficacies of 5- and 14-day primaquine regimens in the prevention of relapses in Plasmodium vivax infections. Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial. Combined chloroquine, sulfadoxine/pyrimethamine and primaquine against Plasmodium falciparum in Central Java, Indonesia.
Primaquine is the only drug available that can eliminate hypnozoites from the liver and prevent relapses of vivax malaria. The World Health Organization recommends a course of 14-21 days depending on region and strain. The National Malaria Control and Eradication Programmes of Pakistan and India have adhered to a 5-day course as their standard as it is deemed more practical to implement and because facility for detecting glucose 6-phosphate dehydrogenase (G6PD) deficiency is seldom available at the periphery. Evidence for the efficacy of the 5-day regimen is controversial or lacking. Two, year-long, randomized controlled trials were undertaken in an Afghan refugee camp in north-western Pakistan using a process of passive case detection and treatment at the camp's clinic: the first trial compared treatment with chloroquine alone versus chloroquine plus 5-days primaquine, the second trial compared chloroquine alone versus chloroquine plus 14-days primaquine. Chloroquine is not hypnozoitocidal and was administered to eliminate the erythrocytic stages and to alleviate clinical symptoms. The daily primaquine dose was 0.25 mg/kg bodyweight and the total chloroquine dose was 25 mg/kg over 3 days. During the first trial 52% (129/250) of the non-primaquine group recorded a 2nd clinical-parasitaemic episode and 23% recorded a 3rd, whereas 51% (128/250) of the 5-days primaquine group reported a 2nd episode and 21% recorded a 3rd. During the second trial 49% (49/100) of the non-primaquine group recorded a 2nd episode and 25% recorded a 3rd, whereas only 32% (32/100) of the 14-days primaquine group recorded a 2nd and only 2% recorded a 3rd. The 5-days primaquine regimen has no value as an anti-relapse therapy and should be abandoned. In extended tests in vivo in which vivax cases (n = 31) were treated with chloroquine 25 mg/kg and 14-days primaquine, there was no parasite recrudescence within 28 days and hence no evidence of resistance to chloroquine. Tafenoquine is an 8-aminoquinoline developed as a more effective replacement for primaquine. In a previous dose-ranging study in Thailand, 3 tafenoquine regimens with total doses ranging from 500 mg to 3000 mg prevented relapse of Plasmodium vivax malaria in most patients when administered 2 days after receipt of a blood schizonticidal dose of chloroquine.
                To improve convenience and to begin comparison of tafenoquine with primaquine, 80 patients with P. vivax infection were randomized to receive 1 of the following 5 treatments 1 day after receiving a blood schizonticidal dose of chloroquine: (A) tafenoquine, 300 mg per day for 7 days (n=18); (B) tafenoquine, 600 mg per day for 3 days (n=19); (C) tafenoquine, 600 mg as a single dose (n=18); (D) no further treatment (n=13); or (E) primaquine base, 15 mg per day for 14 days (n=12). The minimum duration of protocol follow-up was 8 weeks, with additional follow-up to 24 weeks.
                Forty-six of 55 tafenoquine recipients, 10 of 13 recipients of chloroquine only, and 12 of 12 recipients of chloroquine plus primaquine completed at least 8 weeks of follow-up (or had relapse). There was 1 relapse among recipients of chloroquine plus tafenoquine, 8 among recipients of chloroquine only, and 3 among recipients of chloroquine plus primaquine. The rate of protective efficacy (determined on the basis of reduction in incidence density) for all recipients of chloroquine plus tafenoquine, compared with recipients of chloroquine plus primaquine, was 92.6% (95% confidence interval, 7.3%-99.9%; P=.042, by Fisher's exact test).
                Tafenoquine doses as low as a single 600-mg dose may be useful for prevention of relapse of P. vivax malaria in Thailand. The blood stage antimalarial efficacy of primaquine (0.25 mg of base/kg of body weight/day over 14 days) and chloroquine (25 mg of base/kg over 3 days) were compared in 85 adult Thai men with acute Plasmodium vivax malaria. Most (75%) had at least one malaria episode previously. Parasite clearance times after primaquine alone (n = 30) were slower than after chloroquine (n = 30) or combined chloroquine-primaquine (n = 25), but all patients had a satisfactory initial therapeutic response. P. vivax malaria recurred in 10 (17%) of 60 patients followed for > or = 2 months and Plasmodium falciparum malaria developed in another 5 (8%) without reexposure to infection. Recurrences occurred < or = 5 weeks after primaquine treatment (n = 4), suggesting recrudescence, whereas recurrences after chloroquine treatment (n = 6) occurred > or = 5 weeks later, suggesting relapse. Vivax malaria responds well initially to either primaquine or chloroquine. The blood stage antimalarial activity of primaquine may mask chloroquine resistance in combined regimens. Seventy-nine adults with Plasmodium vivax malaria, from the Porto Velho area of Rond nia (western Amazon region, Brazil), gave informed consent to participate in a blind, clinical study of two regimens of treatment with chloroquine (CQ) and primaquine. The effectiveness of the 'classical' regimen (CQ for 3 days, followed by primaquine for 14 days) was compared with that of a 'short' regimen in which the two drugs were given simultaneously for 5 days. There were no cases of recrudescence indicative of CQ resistance (i.e. within 30 days of the first treatment dose) among the 73 patients who each completed a full, supervised course of treatment. However, 10 cases of apparent relapse were observed (all > 60 days after first treatment dose), representing 6.5% (2/31) of the patients who completed 60 days of follow-up after the classical treatment and 26.7% (8/30) of the short-regimen patients who completed the same period of follow-up. PCR-based comparison of parasitic DNA collected pre- and post-treatment was successful for eight of the 10 cases of apparent relapse and indicated that two such cases, both given the short regimen of treatment, were, in fact, probable cases of re-infection rather than of relapse. The results indicate that the classical schedule of treatment with chloroquine and primaquine was more effective at preventing relapses than the short regimen. However, since prolonged treatment with primaquine often produces side-effects that are severe enough to reduce compliance, the short schedule could be a useful alternative for malaria control in endemic areas of the Amazon region. For over 4 decades the antimalarial program in India has been prescribing a 5-day primaquine regimen as an antirelapse therapy to treat Plasmodium vivax malaria. In view of conflicting reports on the effectiveness of this regimen in the Indian subcontinent, and the varying prevalence of P. vivax in various ecosystems in India, the antirelapse efficacy of this regimen was evaluated in Orissa, a malaria endemic state in eastern India where P. falciparum predominates. In 723 cases of P. vivax infection treated with chloroquine alone and followed up weekly for 1 yr, the prevalence of recurrence of parasitaemia with fever was 8.6%. Among another 759 P. vivax cases treated with chloroquine and a 5-day regimen of primaquine at 15 mg/day (adult dose), the recurrence of infection was 6.5%. The difference in recurrence was not significant (P = 0.53). It is important to note that in a great majority of cases of P. vivax in this area, infection did not recur even without treatment with primaquine. This finding, that the use of the 5-day primaquine regimen with chloroquine had no significant advantage over the use of chloroquine alone, undermines the rationale of using primaquine as an antirelapse drug in forested areas with a high prevalence of P. falciparum. Chloroquine remains the drug of choice for the treatment of vivax malaria in Thailand. Mixed infections of falciparum and vivax malaria are also common in South-East Asia. Laboratory confirmation of malaria species is not generally available. This study aimed to find alternative regimens for treating both malaria species by using falciparum antimalarial drugs. From June 2004 to May 2005, 98 patients with Plasmodium vivax were randomly treated with either artemether-lumefantrine (n = 47) or chloroquine (n = 51). Both treatments were followed by 15 mg of primaquine over 14 days. Adverse events and clinical and parasitological outcomes were recorded and revealed similar in both groups. The cure rate was 97.4% for the artemether-lumefantrine treated group and 100% for the chloroquine treated group. We concluded that the combination of artemether-lumefantrine and primaquine was well tolerated, as effective as chloroquine and primaquine, and can be an alternative regimen for treatment of vivax malaria especially in the event that a mixed infection of falciparum and vivax malaria could not be ruled out. Azithromycin has demonstrated activity in a prevention of Plasmodium vivax infection, but no controlled treatment studies have been performed. We conducted a double-blinded trial in P. vivax malaria in which patients were randomized to either azithromycin 1,000 mg q.d. x 3 or chloroquine 600 mg q.d. x 2 then 300 mg on Day 3 followed by primaquine on Days 7 through 20. Eighty-five of 97 (88%) of those on azithromycin and 101 of 102 (99%) of those on chloroquine [difference 11%; 95% CI: -18, -4] were clinically cured at Day 7. The Day 28 results were similar [89% versus 99%, azithromycin versus chloroquine, respectively]. Parasitologic success was seen in 81 of 97 (84%) on azithromycin and 100 of 102 (98%) on chloroquine [difference 14%; 95% CI: -22, -6]. The median parasite clearance time was 55 hours on azithromycin and 20 hours on chloroquine (P < 0.001). Drug-related adverse events were seen in 13 of 98 (13%) on azithromycin and 24 of 102 (24%) on chloroquine (P = 0.062). Resolution of parasitemia was significantly faster with chloroquine compared with azithromycin, but azithromycin was better tolerated. These data provide support for further study of azithromycin to better define its role in the treatment of P. vivax malaria, either alone as second-line treatment or in combination with other active therapies. We studied the antirelapse efficacy of a supervised 14-d 15 mg/d regimen of primaquine therapy (n = 131) compared with no antirelapse therapy (n = 142) in 273 patients with confirmed Plasmodium vivax malaria in Mumbai, India, between July 1998 and April 2000. There were 6/131 (4.6%) recurrences in patients given primaquine compared with 13/142 (9.2%) in those not given antirelapse therapy. In the 14-d primaquine group, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) genotyping analysis of pre- and post-treatment blood samples was done for the 6 patients who had a recurrence of parasitaemia and the results gave a true relapse rate of 2.29% (3/131), 2 samples were classified as reinfections and 1 sample did not amplify. Our results indicate probable resistance to the 14-d regimen of primaquine for the first time in India and illustrate the need to (i) monitor patients given this regimen and (ii) carry out comparative studies between primaquine and new drugs such as tafenoquine and bulaquine for preventing relapses. Vivax malaria accounts for 80% of malaria cases in Mumbai (Bombay) and has high morbidity. In India, the standard treatment to prevent relapses of vivax malaria is a 5-day regimen of primaquine. However, between 1977 and 1997, the efficacy of this treatment declined from approximately 99% to 87%. The efficacy of the 5-day regimen was therefore compared with that of the 14-day regimen currently recommended by the World Health Organization, in Mumbai. The relapse rates observed, over a 6-month period of follow-up, were 0% with the 14-day regimen, 26.7% with the 5-day, and 11.7% when no primaquine treatment was given. The expenditure incurred on the door-to-door dispensing of the 5-day regimen appears to be without benefit. There is an urgent need to review the present strategy for controlling relapses in vivax malaria, at least for the city of Mumbai, and similar studies need to be carried out in other parts of India, to make all anti-relapse strategies more appropriate. Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail.
                Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Delta = 5% difference in proportion of failures).
                Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported.
                Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be administered, dihydroartemisinin-piperaquine provides additional benefit in terms of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment. Chloroquine (CQ) or sulfadoxine-pyrimethamine (SP) monotherapy for Plasmodium falciparum often leads to therapeutic failure in Indonesia. Combining CQ with other drugs, like SP, may provide an affordable, available and effective option where artemisinin-combined therapies (ACT) are not licensed or are unavailable.
                This study compared CQ (n = 29 subjects) versus CQ + SP (with or without primaquine; n = 88) for clinical and parasitological cure of uncomplicated falciparum malaria in the Menoreh Hills region of southern Central Java, Indonesia. Gametocyte clearance rates were measured with (n = 56 subjects) and without (n = 61) a single 45 mg dose of primaquine (PQ).
                After 28 days, 58% of subjects receiving CQ had cleared parasitaemia and remained aparasitaemic, compared to 94% receiving CQ combined with SP (p < 0.001). Msp-2 genotyping permitted reinfection-adjusted cure rates for CQ and CQ combined with SP, 70% and 99%, respectively (p = 0.0006).
                Primaquine exerted no apparent affect on cure of asexual stage parasitaemia, but clearly accelerated clearance of gametocytes. CQ combined with SP was safe and well-tolerated with superior efficacy over CQ for P. falciparum parasitaemia in this study.
Primaquine (15 mg/day for 14 days) plus chloroquine is more effective than chloroquine alone or primaquine (15 mg/day for 5 days) plus chloroquine in preventing relapses of vivax malaria. Primaquine (five days) plus chloroquine appears no better than chloroquine. Countries should follow the WHO's recommendation for 14-day primaquine plus chloroquine regimen. Alternative regimens need to be evaluated in randomized controlled trials, which should also consider variations in regional P. vivax strains and the possibility of primaquine resistance, reinfection, and adherence in those who relapse.