Primaquine — Finding Its Niche for Malaria Chemoprophylaxis

By Mary-Louise Scully, MD

Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA.

Dr. Scully reports no financial relationships relevant to this field of study.

A symposium on Plasmodium Vivax (P. vivax) malaria was held at the recent annual meeting of the American Society of Tropical Medicine and Hygiene in Philadelphia. Dr. Eli Schwartz of the Sheba Medical Center in Israel presented his experiences with relapsing P. vivax malaria in travelers to the Omo River in southern Ethiopia, a popular destination among Israeli travelers for adventure river rafting. The majority of malaria in sub-Saharan Africa is caused by Plasmodium falciparum, but in Ethiopia, 25% to 35% of malaria cases can be secondary to P. vivax. In 1998, Schwartz reported that despite appropriate use of mefloquine for prophylaxis, up to 50% of travelers returning from the Omo River trips were infected with P. vivax. In nearly all the patients, the first clinical episode occurred greater than three months after exposure.1

In a subsequent study of travelers to the Omo River, patients who had used primaquine for malaria prophylaxis were compared to those using doxycycline or mefloquine. Of the 106 travelers who received primaquine, 5.7% developed malaria. By comparison, in the 19 doxycycline recipients, 53% developed malaria, and in the 25 mefloquine recipients, 52% developed P. vivax malaria. It is noteworthy that among the small number of primaquine-failure cases, a higher proportion of P. falciparum infection was observed.2

Looking beyond Israeli patients, Schwartz and colleagues showed that up to one-third of all reported cases of malaria in both Israel and the United States were late onset P. vivax or P. ovale that occurred despite adequate use of blood-stage malaria chemoprophylaxis. 3 The key point is that all our commonly used malaria chemoprophylactic regimens (chloroquine, mefloquine, doxycycline, and atovaquone-proguanil) prevent blood-stage infection but do not prevent relapses of vivax malaria because they do not eliminate the liver-stage parasites (hypnozoites). Only primaquine is active on liver hypnozoites of P. vivax and P. ovale, and primaquine is truly the only agent available to prevent late relapses.

In the November 2007 issue of Journal of Travel Medicine, Maguire and Llewellyn report a case of vivax malaria after six months of daily atovaquone-proguanil in a 22-year-old soldier stationed in Afghanistan.4 The patient was not compliant with his atovaquone-proguanil upon departure from Afghanistan, but, regardless, late relapse with P. vivax would not have been prevented by atovaquone-proguanil. The case highlights the consideration for expanding the role of primaquine as a primary prophylaxis regimen.

Specifications for the use of primaquine were detailed by Dr. Alan Magill of the Walter Reed Army Institute of Research. The current strategy for prevention of P. vivax and P. ovale relapses include the addition of two weeks of primaquine (after appropriate blood-stage malaria chemoprophylaxis) for travelers with prolonged or intense exposure in P. vivax and P. ovale areas. The appropriate terminology for this is now presumptive anti-relapse treatment (PART). Patients need to be tested prior to use of primaquine for G6PD deficiency, as primaquine causes acute hemolysis in patients with hereditary forms of G6PD deficiency. Primaquine is contraindicated in pregnancy. Side effects are usually gastrointestinal symptoms, such as nausea and vomiting, that are lessened by its administration with food.

The optimal dose of primaquine appears to be 6 mg/kg (base), not to exceed 30 mg (base) daily, whereas previous recommendations were lower (15 mg base daily). Tropical P. vivax strains in Southeast Asia and Papua New Guinea seem to require these higher doses of 6 mg/kg for effective cure of relapse, which prompted the change in the current CDC recommendations. Even at this dosage, the occasional therapeutic failure can occur.

Primaquine used as a primary prophylactic regimen in areas of high P. vivax transmission offers the advantage of preventing late relapses. This use is technically off-label, but primaquine (30 mg base daily) can be used starting one day before, each day during, and for seven days after travel to a malaria risk area. The CDC now lists primaquine as an alternative regimen for those patients with special circumstances or patients who are unable to tolerate other antimalarials. The caution to use this regimen first-line is likely appropriate based on the concern about using primaquine as prophylaxis in areas with a high P. falciparum transmission rates. Primaquine has only very modest blood-stage activity, so if parasites break through the liver and into the blood, then clinical cases of falciparum malaria can occur. This was found to be the case in the Omo River group, where four of the six breakthrough malaria cases in the primaquine group were, indeed, P. falciparum.2

We are left with the realization that nothing is perfect in the realm of malaria prevention. Travel medicine physicians should make patients aware of the possibility of clinical illness despite suppressive malaria chemoprophylaxis, even months after their trip. Also, a course of presumptive anti-relapse treatment (PART) should be considered if their travel took them to high risk areas for P. vivax. Vivax malaria is especially common in India, Indochina, Latin America, and the Philippine, Indonesian and New Guinean archipelagos.5 Proper clinical decisions will need to take into consideration the specific destination and risk by species to best define the right choice of malaria chemoprophylaxis for each individual traveler.

References:

  1. Schwartz E, Sidi Y. New Aspects of Malaria Imported from Ethiopia. Clin Infect Dis. 1998; 26:1089-1091.
  2. Schwartz E, Regev-Yochay G. Primaquine as Prophylaxis for Malaria for Nonimmune Travelers: A Comparison with Mefloquine and Doxycycline. Clin Infect Dis. 1999; 29:1502-1506.
  3. Schwartz E et al. Delayed Onset of Malaria - Implications for Chemoprophylaxis in Travelers. NEJM. 2003; 349:1510-1516.
  4. Maguire JD, Llewellyn DM. Relapsing Vivax Malaria After 6 Months of Daily Atovaquone/Proguanil in Afghanistan: The Case for Expanded Use of Primaquine as a Causal Prophylactic. J Travel Med. 2007;14(6):411-414.
  5. Baird JK, Hoffman SL. Primaquine Therapy for Malaria. Clin Infect Dis. 2004; 39:1,336-1,345