570 TRANSACTIONSOFTHE ROYAL SOCIETYOFTROPICAL MEDICINE AND HYGIENE (1992) 86, CORRESPONDENCE
(Correspondence
1
Chloroquine-resistant Plasmodium vivaxin Brazil? Garavelli & Corti (1992: Transactions, 86, 128) recently reported an apparent case of chloroqume-resistant Plasmodium vivax in a patient from Brazil, and we would like to raise some comments concerning the authors’ findings and their claim about drug resistance. According to their description of the case and to the diagnostic and therapeutic procedures carried out, we suggest that they may have failed to distinguish between episodes of malaria relapse and chloroquine resistance. The permanence of pre-erythrocytic stages (hypnozoites) in liver tissue for extended periods of time is well documented in P. vivax (Krotoski et al.. 1982: American Journal of Tropical Medicine and Hy&ene, 31, 12911293). Blood-starre narasites are cleared either bv successful Geatment wytg schizontocidal drugs or b$ spontaneous elimination between malaria episodes. The number of, and interval between, relapsing episodes seem to depend on the climatic zone, with tropical strains producing frequent relapses with short intervals, while ihe oppoiite occurs in the temperate zones (Contacos et al., 1972: America1 Townal of Trobical Medicine and Hvgiene, 21, 707-712): Relaps& are commonly associatgd with prolonged intervals between episodes, while reappearance of blood parasites due to resistance is usually manifested within a month after treatment. The regular pattern of repeated malaria episodes every 4 months, as described in the case from Brazil, tends to suggest the uresence of a Chesson-like relansing strain of P. uivax. Relapsing episodes after treaimegt with chloroquine alone have been renorted bv Mason in El Salvador (1975: American Journal Lf Tropical Medicine and Hygiene, 24, 581-585). We have recently found an area in souther Mexico (unpublished observations) where repeated malaria episodes occur frequently. Rapid proliferation of this type of relapsing strain is generating increasing public health concern (Schuurkamp et al., 1992: Transactions, 86,121-122). Recommended treatment of P. vivax malaria is based on chloroquine and primaquine (Peters, 1988: Chemotherapy and Drug Resistance in Malaria. London: Academic I%ess). Chloroquine is a schizontocidal drug that has its main effects on the asexual blood stages of Plasmodium, while primaquine has been claimid to have some effect on gametocytes and on liver stages. When evaluating the effect of a drug combination that has different effects on the parasite, it is important to identify the origin of the parasitaemia, either from the permanence of sub-clinical blood stages or from the occurrence of relapses from tissue parasites. Drug resistance has been defined as the ability of a parasite strain to survive and/or multiDlv desnite the administration and absorption of a drug gven in doses equal to or higher than those usually recommended (WHO, 1973: Chemotherapy of Malaria and Resistance to Antimalarials. Geneva: World Health Orzanization. Technical Renort Series. no. 529). Although no extended surveillance was conducted between the malaria episodes, the apparent clearance of parasitaemia after each of the episodes in the Brazilian case does not conform to the definition of chloroaine resistance. The occurrence of resistance of P. vivax was suggested by Rieckmann et al. (1989: Lancet, ii, 1183-1184), after finding that chloroquine prophylaxis did not protect soldiers against malaria in Papua New Guinea. Chloroquine resistance in P. vivax infections was more recently documented in Papua New Guinea in 2 patients who received 2400 mg of drug base over a period of 4 d (Schuurkamp et al., 1992: Transactions, 86, 121-122). Parasites were still present 96 h after the onset of treatment, in spite of achieving blood plasma concentrations of chloroquine lo-fold higher than those that should have completely inhibited parasitaemia. 1
On the other hand, primaquine failure has been documented in several cases. The frequency of failure to produce radical cure even after a full 14 d course of primaquine may be high with P. vivax Chesson strains, with up to 30% of infected people suffering subsequent malaria episodes (Savioli et al., 1985: British Medical Journal, 291, 23-24). In Mexico, Gomez-Mendoza mimeographed document no. (1965: WHO WHOiMALi527.65) found that nearly 10% of people receiving 14 d, and 20% of those having 5 d, primaquine treatment had a second episode of malaria. In a report that is geographically more relevant to the Brazilian case, Arias & Corredor (1989: Tropical Medicine and Parasitology, 40, 21-23) suggested &at drug resistance could be emerging in Colombia, based on their findings that more new (relapsing) infections were occurring in patients from the Amazon Basin. following 14 d radical treatment under conditions’ that pr&luded re-infection. These findings suggest that the presence of relapsing strains of P. vivax in the American region is not an infrequent occurrence. Parasites strains differ in their susceptibility to drugs even when resistance, as already defined, cannot be invoked. In the present case, if resistance existed, it would have been directed against primaquine and not chloroquine. Enrique G. Loyola Mario H. Rodriguez Centro de Investigacidn de Paludismo Apartado Postal 537 Tapachula, Chiapas 30700 M&co 5 June 1992 Garavelli and Corti 11992: Transactions. 86. 128) reported what they believed to be the first c&e df Plaimodium vivaw resistant to chloroquine in Brazil. However, there are considerable doubts about such a conclusion. The patient described by them suffered from several attacks of vivax malaria at 3-4 months intervals (January 1991. 21 Am-i1 1991. 14 Auaust 1991). in suite of beine treatid witL chloroquine pks primaiuine.’ In our opiy nion, the patient suffered from relapses, typical of vivax malaria, due to pesistence of hypnozoites in the liver, and not from recrudescences due to persistence of chloroauine-resistant asexual ervthrocvtic forms of P. vivax. as
(Correspondence
1
Chloroquine-resistant Plasmodium vivaxin Brazil? Garavelli & Corti (1992: Transactions, 86, 128) recently reported an apparent case of chloroqume-resistant Plasmodium vivax in a patient from Brazil, and we would like to raise some comments concerning the authors’ findings and their claim about drug resistance. According to their description of the case and to the diagnostic and therapeutic procedures carried out, we suggest that they may have failed to distinguish between episodes of malaria relapse and chloroquine resistance. The permanence of pre-erythrocytic stages (hypnozoites) in liver tissue for extended periods of time is well documented in P. vivax (Krotoski et al.. 1982: American Journal of Tropical Medicine and Hy&ene, 31, 12911293). Blood-starre narasites are cleared either bv successful Geatment wytg schizontocidal drugs or b$ spontaneous elimination between malaria episodes. The number of, and interval between, relapsing episodes seem to depend on the climatic zone, with tropical strains producing frequent relapses with short intervals, while ihe oppoiite occurs in the temperate zones (Contacos et al., 1972: America1 Townal of Trobical Medicine and Hvgiene, 21, 707-712): Relaps& are commonly associatgd with prolonged intervals between episodes, while reappearance of blood parasites due to resistance is usually manifested within a month after treatment. The regular pattern of repeated malaria episodes every 4 months, as described in the case from Brazil, tends to suggest the uresence of a Chesson-like relansing strain of P. uivax. Relapsing episodes after treaimegt with chloroquine alone have been renorted bv Mason in El Salvador (1975: American Journal Lf Tropical Medicine and Hygiene, 24, 581-585). We have recently found an area in souther Mexico (unpublished observations) where repeated malaria episodes occur frequently. Rapid proliferation of this type of relapsing strain is generating increasing public health concern (Schuurkamp et al., 1992: Transactions, 86,121-122). Recommended treatment of P. vivax malaria is based on chloroquine and primaquine (Peters, 1988: Chemotherapy and Drug Resistance in Malaria. London: Academic I%ess). Chloroquine is a schizontocidal drug that has its main effects on the asexual blood stages of Plasmodium, while primaquine has been claimid to have some effect on gametocytes and on liver stages. When evaluating the effect of a drug combination that has different effects on the parasite, it is important to identify the origin of the parasitaemia, either from the permanence of sub-clinical blood stages or from the occurrence of relapses from tissue parasites. Drug resistance has been defined as the ability of a parasite strain to survive and/or multiDlv desnite the administration and absorption of a drug gven in doses equal to or higher than those usually recommended (WHO, 1973: Chemotherapy of Malaria and Resistance to Antimalarials. Geneva: World Health Orzanization. Technical Renort Series. no. 529). Although no extended surveillance was conducted between the malaria episodes, the apparent clearance of parasitaemia after each of the episodes in the Brazilian case does not conform to the definition of chloroaine resistance. The occurrence of resistance of P. vivax was suggested by Rieckmann et al. (1989: Lancet, ii, 1183-1184), after finding that chloroquine prophylaxis did not protect soldiers against malaria in Papua New Guinea. Chloroquine resistance in P. vivax infections was more recently documented in Papua New Guinea in 2 patients who received 2400 mg of drug base over a period of 4 d (Schuurkamp et al., 1992: Transactions, 86, 121-122). Parasites were still present 96 h after the onset of treatment, in spite of achieving blood plasma concentrations of chloroquine lo-fold higher than those that should have completely inhibited parasitaemia. 1
On the other hand, primaquine failure has been documented in several cases. The frequency of failure to produce radical cure even after a full 14 d course of primaquine may be high with P. vivax Chesson strains, with up to 30% of infected people suffering subsequent malaria episodes (Savioli et al., 1985: British Medical Journal, 291, 23-24). In Mexico, Gomez-Mendoza mimeographed document no. (1965: WHO WHOiMALi527.65) found that nearly 10% of people receiving 14 d, and 20% of those having 5 d, primaquine treatment had a second episode of malaria. In a report that is geographically more relevant to the Brazilian case, Arias & Corredor (1989: Tropical Medicine and Parasitology, 40, 21-23) suggested &at drug resistance could be emerging in Colombia, based on their findings that more new (relapsing) infections were occurring in patients from the Amazon Basin. following 14 d radical treatment under conditions’ that pr&luded re-infection. These findings suggest that the presence of relapsing strains of P. vivax in the American region is not an infrequent occurrence. Parasites strains differ in their susceptibility to drugs even when resistance, as already defined, cannot be invoked. In the present case, if resistance existed, it would have been directed against primaquine and not chloroquine. Enrique G. Loyola Mario H. Rodriguez Centro de Investigacidn de Paludismo Apartado Postal 537 Tapachula, Chiapas 30700 M&co 5 June 1992 Garavelli and Corti 11992: Transactions. 86. 128) reported what they believed to be the first c&e df Plaimodium vivaw resistant to chloroquine in Brazil. However, there are considerable doubts about such a conclusion. The patient described by them suffered from several attacks of vivax malaria at 3-4 months intervals (January 1991. 21 Am-i1 1991. 14 Auaust 1991). in suite of beine treatid witL chloroquine pks primaiuine.’ In our opiy nion, the patient suffered from relapses, typical of vivax malaria, due to pesistence of hypnozoites in the liver, and not from recrudescences due to persistence of chloroauine-resistant asexual ervthrocvtic forms of P. vivax. as
