Ashley, E. and F. Nosten, Management of Multiple Drug-Resistant Malaria, in Management of Multi Drug-Resistant Infections, S.H. Gillespie, Editor. 2004, Humana Press Inc: Totowa, NJ. p. 319-39.

Ashley, E., R. McGready, S. Proux, and F. Nosten, Malaria, in Essentials in Travel Medicine, J. Zuckerman, Editor. 2004, Wiley.

Myint, H.Y., P. Tipmanee, F. Nosten, N.P. Day, S. Pukrittayakamee, S. Looareesuwan, and N.J. White, A systematic overview of published antimalarial drug trials. Trans R Soc Trop Med Hyg, 2004. 98(2): p. 73-81.Pubmed
Systematic database searches identified 435 antimalarial drug treatment trials, involving 82,616 patients, conducted and published between 1966 and December 2002. Of these trials 72% were randomised; 64 (15%) trials involved severe malaria, 47 (11%) studied Plasmodium vivax, 3 Plasmodium malariae or Plasmodium ovale, and the remainder (74%) assessed treatment responses in uncomplicated falciparum malaria. Twelve trials (2.7%) specifically evaluated antimalarial treatments in pregnant women. Overall 49% of trials were conducted in Asia (29% from Thailand alone) and 42% in Africa. Half of all the patients studied had been in trials published in the past 7 years. There has been a recent rise in the proportion of trial enrolling children, and a tripling in the average number of patients recruited per trial (from approximately 100 in the 1970s to 300 currently). Chloroquine was given to over half the patients in antimalarial drug trials (n = 53552) compared with artemisinin derivatives (n = 12463), mefloquine-sulphadoxine-pyrimethamine (n = 9153), mefloquine (n = 5546) and sulphadoxine-pyrimethamine (n = 5909). The quality of safety and efficacy data for recently evaluated drugs contrasts with a relative paucity of data for older 'established' compounds.

Chaisavaneeyakorn, S., P. Kongtawelert, P. Angkasekwinai, R. McGready, F. Nosten, and S.C. Chaiyaroj, Inhibitory activities of sulfated proteoglycans on chondroitin sulfate A-mediated cytoadherence of Plasmodium falciparum isolates from Thailand. Am J Trop Med Hyg, 2004. 70(2): p. 149-57.Pubmed
Chondroitin sulfate A (CSA) is an important receptor for Plasmodium falciparum-infected erythrocytes in the placenta. To study the molecular interaction between parasitized erythrocytes (PE) to CSA, we performed in vitro cytoadherence inhibition assays of PE infected with wild and laboratory isolates of P. falciparum to CSA using various glycosaminoglycans (GAGs). Marked decrease in PE adhesion to immobilized CSA and CSA-expressed cells was achieved with soluble chondroitin sulfate D (CSD) and chondroitin sulfate E (CSE) at low concentrations. The effect was dose dependent with the degree of inhibition exceeded that of soluble CSA in certain clinical isolates. The results suggested the influence of oversulfation of CS variant chains on PE adherence to CSA. Interestingly, PE of the tested wild isolates could adhere to immobilized CSD and CSE at different levels while PE of CSA-selected laboratory lines could not. Partial inhibitory activity was observed when chondroitin sulfate C (CSC), chondroitin sulfate B (CSB), and polyolpolysulfate were used even at high concentrations. Keratan sulfate, colominic acid, and Suramine were unable to inhibit PE adherence. Taken together, the results confirm that the 4-sulfate amino sugar moiety, as well as the basic disaccharide structure of N-acetylgalactosamine linked to glucuronic acid, may influence the degree of this molecular interaction. However, other sulfation patterns that could influence the interaction could not be overlooked, as in the case of CSD which contains 2-O-sulfation at glucuronic acid. Studies using pentosan polysulfate, an oversulfated molecule with a xylan backbone, as an inhibitor also showed a reduction of PE adherence of most isolates tested. Thus, only the sulfate content and pattern of this molecule could affect the adhesive interactions. In addition, difference in capacity of low molecular weight heparins to inhibit CSA-mediated PE cytoadherence of clinical isolates was also observed, thereby providing evidence on the heterogeneity in cytoadherence characteristics of maternal parasite isolates as well as their therapeutic potentials.

Smithuis, F., I. van der Broek, N. Katterman, M.K. Kyaw, A. Brockman, S. Lwin, and N.J. White, Optimising operational use of artesunate-mefloquine: a randomised comparison of four treatment regimens. Trans R Soc Trop Med Hyg, 2004. 98(3): p. 182-92.Pubmed
A randomised trial was conducted in adults and children (> 1 year old) with acute falciparum malaria in Western Myanmar to compare the operational effectiveness of 4 different artesunate-mefloquine combinations. All regimens were well tolerated. During 42 days follow-up polymerase chain reaction genotyping-confirmed recrudescence occurred in 11 of 187 (5.9%) patients who received observed single low-dose mefloquine (15 mg/kg) and artesunate (4 mg/kg), 7 of 192 (3.6%) patients following observed single high-dose mefloquine (25 mg/kg) and artesunate (4 mg/kg), 7 of 180 (3.9%) patients following observed artesunate 4 mg/kg on day 0 plus self-administered mefloquine 15 mg/kg on day 1 and 10 mg/kg on day 2 with artesunate 4 mg/kg/day on day 1 and 2, and none of 177 patients who received this 3 d regimen under direct observation (P = 0.01). Compared with 3 d treatment regimens, single dose treatments were followed by significantly more P vivax infections during the 42 d follow-up (P = 0.009). Post treatment anaemia (haemoglobin < 10 g/dL) was reduced by the 3 d regimens. Gametocyte appearance was low with all 4 regimens. Single dose observed mefloquine-artesunate regimens were very effective, but the 3 d artesunate-mefloquine regimen is the best treatment for acute falciparum malaria in Western Myanmar. Active measures to ensure absorption and improve adherence will be necessary to realise this advantage operationally.

Nacher, M., V.I. Carrara, R. McGready, E. Ashley, J.V. Nguen, K.L. Thwai, S. Looareesuwan, and F. Nosten, Seasonal fluctuations in the carriage of Plasmodium vivax gametocytes in Thailand. Ann Trop Med Parasitol, 2004. 98(2): p. 115-20.Pubmed
To study the influence of season on Plasmodium vivax gametocyte carriage, the relationship between monthly rainfall and the proportion of P. vivax patients with detectable gametocytaemia was analysed. Most of the data used came from 6807 aggregated observations collected, in a refugee camp on the Thai-Burmese border, between January 2000 and December 2002. There was a positive correlation between rainfall and the incidence of P. vivax infection (Spearman's rho=+0.42; P =0.01) but the prevalence of gametocyte carriage among those with P. vivax infection was negatively correlated with rainfall (Spearman's rho=-0.58; P <0.001). The latter, negative correlation remained significant after controlling for the proportion of visitors relative to camp residents (P =0.003). Migrations, changes in transmission patterns, seasonal haematological changes, and ultraviolet immunosuppression are discussed as potential explanations for these observations.

Brockman, A., S. Singlam, L. Phiaphun, S. Looareesuwan, N.J. White, and F. Nosten, Field evaluation of a novel colorimetric method--double-site enzyme-linked lactate dehydrogenase immunodetection assay--to determine drug susceptibilities of Plasmodium falciparum clinical isolates from northwestern Thailand. Antimicrobial Agents and Chemotherapy, 2004. 48(4): p. 1426-9.Pubmed
A double-site enzyme-linked lactate dehydrogenase enzyme immunodetection assay was tested against field isolates of Plasmodium falciparum for assessing in vitro drug susceptibilities to a wide range of antimalarial drugs. Its sensitivity allowed the use of parasite densities as low as 200 parasites/microl of blood. Being a nonisotopic, colorimetric assay, it lies within the capabilities of a modest laboratory at the district level.

Nosten, F. and E. Ashley, The detection and treatment of Plasmodium falciparum malaria: Time for change. Journal of Postgraduate Medicine, 2004. 50(1): p. 35-9.Pubmed
In most countries where malaria is endemic, P. falciparum malaria is on the rise. This is primarily due to the spread of drug-resistant strains. Drug resistance is mediated by spontaneous changes in the parasite genome that allow resistant parasites to escape the action of the drugs. The spread of drug resistance increases the transmission of malaria parasites. The consequences for the populations at risk are profound both in terms of consequences for health and economy. In order to halt the progression of drug resistance, we need to change the way antimalarials are used. As in tuberculosis and HIV/AIDS, we must use a combination of drugs for the treatment of malaria. Taking into account the pharmacokinetic and pharmacodynamic properties of the various anti-malarial agents, artemisinin-based combination therapy (ACT) seems to be the best option. This strategy should be used in conjunction with early diagnosis and appropriate vector control measures to achieve reduction in the emergence and spread of drug resistance.

White, N., F. Nosten, A. Bjorkman, K. Marsh, and R.W. Snow, WHO, the Global Fund, and medical malpractice in malaria treatment. Lancet, 2004. 363(9415): p. 1160.Pubmed

Checchi, F., P. Piola, C. Kosack, E. Ardizzoni, D. Klarkowski, E. Kwezi, G. Priotto, S. Balkan, N. Bakyaita, A. Brockman, and J.P. Guthmann, Antimalarial efficacy of sulfadoxine-pyrimethamine, amodiaquine and a combination of chloroquine plus sulfadoxine-pyrimethamine in Bundi Bugyo, western Uganda. Trop Med Int Health, 2004. 9(4): p. 445-50.Pubmed
Summary We report below an in vivo antimalarial efficacy study conducted in 2002 in Bundi Bugyo, a district of western Uganda housing a large displaced population. We tested sulfadoxine-pyrimethamine (SP), amodiaquine (AQ) and the combination chloroquine plus SP (CQ + SP). A total of 268 children with uncomplicated Plasmodium falciparum malaria were followed-up for 28 days according to WHO recommendations, with PCR genotyping to distinguish late recrudescences from re-infections. PCR-adjusted failure proportions at day 28 were 37.0% (34/92, 95% CI 27.1-47.7) in the SP group, 20.6% (14/68, 95% CI 11.7-32.1) in the AQ group and 22.8% (18/79, 95% CI 14.1-33.6) in the CQ + SP group. Early failures were particularly frequent in the SP group (15.2%). Clearance of gametocytes was slower in the SP and CQ + SP groups than in the AQ group. This study suggests that, in Bundi Bugyo, CQ + SP (Uganda's first-line regimen) will need to be replaced by a more efficacious regimen. Across Uganda, the deployment of SP containing combinations may not be a feasible long-term strategy. For Bundi Bugyo, we recommend a combination of artesunate and AQ. Our study also confirms previous findings that resistance is considerably underestimated by 14-day follow-ups. Antimalarial policy decisions should therefore be based on 28-day studies, with PCR adjustment to distinguish re-infections.

Brabin, B.J., C. Romagosa, S. Abdelgalil, C. Menendez, F.H. Verhoeff, R. McGready, K.A. Fletcher, S. Owens, U. D'Alessandro, F. Nosten, P.R. Fischer, and J. Ordi, The sick placenta-the role of malaria. Placenta, 2004. 25(5): p. 359-78.Pubmed
The human placenta is an ideal site for the accumulation of Plasmodium falciparum malaria parasites, and as a consequence serious health problems arise for the mother and her baby. The pathogenesis of placental malaria is only partially understood, but it is clear that it leads to a distinct epidemiological pattern of malaria during pregnancy. The objectives of this review are: (1) To review recent data on the epidemiology of malaria in pregnancy, with emphasis on placental malaria; (2) to describe the pathological changes and immunological factors related to placental malaria; and (3) to discuss briefly the functional consequences of this infection for the mother and her baby. The review attempts to bring together local events at the maternal-fetal interface which encompass immunological and pathological processes which relate to the epidemiological pattern of malaria in pregnancy in areas of both high and low malaria transmission. An integrated understanding of the epidemiological, immunological and pathological processes must be achieved in order to understand how to control malaria in pregnancy. The yearly exposure of at least 50 million pregnancies to malaria infection makes it the commonest and most recurrent parasitic infection directly affecting the placenta. These statistics and our limited understanding of its pathogenesis suggest the research priorities on this subject.

McGready, R., B.B. Davison, K. Stepniewska, T. Cho, H. Shee, A. Brockman, R. Udomsangpetch, S. Looareesuwan, N.J. White, S.R. Meshnick, and F. Nosten, The Effects of Plasmodium Falciparum and P. Vivax Infections on Placental Histopathology in an Area of Low Malaria Transmission. Am J Trop Med Hyg, 2004. 70(4): p. 398-407.Pubmed
Placental histopathology was studied in a cohort of 204 women living in an area of low Plasmodium falciparum and P. vivax malaria transmission. Detection of malaria antenatally was active, by weekly peripheral blood smears, and all infections were treated. Significant histopathologic placental malaria changes (increased malaria pigment, cytotrophoblastic prominence, and presence of parasites) were found only in a minority of women who had P. falciparum infections in pregnancy. These changes were significantly more frequent in women with evidence of peripheral blood infection close to delivery and only in these cases were placental inflammatory cells increased. Antenatal P. vivax infection was associated only with the presence of malaria pigment in the placenta. All placental infections diagnosed by blood smear and 32.4% (12 of 37) diagnosed by histopathology were associated with patent peripheral parasitemia. This study indicates that prompt treatment of peripheral parasitemias during pregnancy limits placental pathology. The effect on birth weight reduction may not result from irreversible placental changes but from the acute insult of infection. These findings emphasize the importance of treating malaria in pregnancy promptly with effective antimalarial drugs.

Nacher, M., V.I. Carrara, E. Ashley, R. McGready, R. Hutagalung, J.V. Nguen, K.L. Thwai, S. Looareesuwan, and F. Nosten, Seasonal variation in hyperparasitaemia and gametocyte carriage in patients with Plasmodium falciparum malaria on the Thai-Burmese border. Trans R Soc Trop Med Hyg, 2004. 98(5): p. 322-8.Pubmed
Between January 2000 and December 2002 monthly rainfall was correlated with the proportion of patients with hyperparasitaemic Plasmodium falciparum malaria and with the proportion of patients with P. falciparum gametocytes. During the observation period 6953 cases of P. falciparum malaria were treated at the Shoklo Malaria Research Unit in Maela refugee camp on the Thai-Burmese border. Three hundred and seventy-five of these patients had >/=4% of parasitized red blood cells. Although there were more monthly malaria cases in the rainy season, rainfall was negatively correlated with the proportion of patients with hyperparasitaemia (Spearman's [Formula: see text], [Formula: see text] ), and the proportion of gametocyte carriers among P. falciparum cases, (Spearman's [Formula: see text], [Formula: see text] ). After controlling for age and the origin of the patient, the odds ratio for developing hyperparasitaemia during the dry season was 1.6 (95% CI 1.14-2.2; [Formula: see text] ). The adjusted odds ratio for gametocyte carriage during the dry season was 1.3 (95% CI 1.03-1.6; [Formula: see text] ). Migrations, changes in transmission patterns, the haematological burden of cumulative infections, and ultraviolet immunosuppression are discussed as potential explanations for these observations.

van den Broek, I.V., S. van der Wardt, L. Talukder, S. Chakma, A. Brockman, S. Nair, and T.C. Anderson, Drug resistance in Plasmodium falciparum from the Chittagong Hill Tracts, Bangladesh. Trop Med Int Health, 2004. 9(6): p. 680-7.Pubmed
OBJECTIVE: To assess the efficacy of antimalarial treatment and molecular markers of Plasmodium falciparum resistance in the Chittagong Hill Tracts of Bangladesh. METHODS: A total of 203 patients infected with P. falciparum were treated with quinine 3 days plus sulphadoxine/pyrimethamine (SP) combination therapy, and followed up during a 4-week period. Blood samples collected before treatment were genotyped for parasite mutations related to chloroquine (pfcrt and pfmdr1 genes) or SP resistance (dhfr and dhps). RESULTS: Of 186 patients who completed follow-up, 32 patients (17.2%) failed to clear parasitaemia or became positive again within 28 days after treatment. Recurring parasitaemia was related to age (chi(2) = 4.8, P < 0.05) and parasite rates on admission (t = 3.1, P < 0.01). PCR analysis showed that some of these cases were novel infections. The adjusted recrudescence rate was 12.9% (95% CI 8.1-17.7) overall, and 16.6% (95% CI 3.5-29.7), 15.5% (95% CI 8.3-22.7) and 6.9% (95% CI 0.4-13.4) in three age groups (<5 years, 5-14, > or =15). The majority of infections carried mutations associated with chloroquine resistance: 94% at pfcrt and 70% at pfmdr. Sp-resistant genotypes were also frequent: 99% and 73% of parasites carried two or more mutations at dhfr and dhps, respectively. The frequency of alleles at dhfr, dhps and pfmdr was similar in cases that were successfully treated and those that recrudesced. CONCLUSIONS: The clinical trial showed that quinine 3-days combined to SP is still relatively effective in the Chittagong Hill Tracts. However, if this regimen is continued to be widely used, further development of SP resistance and reduced quinine sensitivity are to be expected. The genotyping results suggest that neither chloroquine nor SP can be considered a reliable treatment for P. falciparum malaria any longer in this area of Bangladesh.

Price, R.N., A.C. Uhlemann, A. Brockman, R. McGready, E. Ashley, L. Phaipun, R. Patel, K. Laing, S. Looareesuwan, N.J. White, F. Nosten, and S. Krishna, Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet, 2004. 364(9432): p. 438-47.Pubmed
BACKGROUND: The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. METHODS: The relation between polymorphisms in the P falciparum multidrug resistant gene 1 (pfmdr1) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 samples from patients with falciparum malaria studied prospectively over 12 years. pfmdr1 copy number was assessed by a robust real-time PCR assay. Single nucleotide polymorphisms of pfmdr1, P falciparum chloroquine resistance transporter gene (pfcrt) and P falciparum Ca2+ ATPase gene (pfATP6) were assessed by PCR-restriction fragment length polymorphism. FINDINGS: Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine, and also to reduced artesunate sensitivity in vitro. In a Cox regression model with control for known confounders, increased pfmdr1 copy number was associated with an attributable hazard ratio (AHR) for treatment failure of 6.3 (95% CI 2.9-13.8, p<0.001) after mefloquine monotherapy and 5.4 (2.0-14.6, p=0.001) after artesunate-mefloquine therapy. Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro, but not in vivo. INTERPRETATION: Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria. RELEVANCE TO PRACTICE: Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with mefloquine. Increase in pfmdr1 copy number predicts failure even after chemotherapy with the highly effective combination of mefloquine and 3 days' artesunate. Monitoring of pfmdr1 copy number will be useful in epidemiological surveys of drug resistance in P falciparum, and potentially for predicting treatment failure in individual patients.

Mayxay, M., M. Khanthavong, N. Lindegardh, S. Keola, M. Barends, T. Pongvongsa, R. Yapom, A. Annerberg, S. Phompida, R. Phetsouvanh, N.J. White, and P.N. Newton, Randomized comparison of chloroquine plus sulfadoxine-pyrimethamine versus artesunate plus mefloquine versus artemether-lumefantrine in the treatment of uncomplicated falciparum malaria in the Lao People's Democratic Republic. Clin Infect Dis, 2004. 39(8): p. 1139-47.Pubmed
BACKGROUND: Recent clinical trials in the Lao People's Democratic Republic have demonstrated that chloroquine and sulfadoxine-pyrimethamine, which are national malaria treatment policy, are no longer effective in the treatment of uncomplicated Plasmodium falciparum malaria. METHODS: A randomized comparison of 3 oral antimalarial combinations--chloroquine plus sulfadoxine-pyrimethamine versus artesunate plus mefloquine versus artemether-lumefantrine--with 42-day follow-up period, was conducted among 330 patients with acute uncomplicated falciparum malaria in southern Laos. RESULTS: The 42-day cure rates, as determined by intention-to-treat analysis and adjusted for reinfection, were 100%, 97%, and 93% for the groups receiving artesunate plus mefloquine, artemether-lumefantrine, and chloroquine plus sulfadoxine-pyrimethamine, respectively. Of 8 patients receiving chloroquine plus sulfadoxine-pyrimethamine who experienced treatment failure, 6 had early treatment failure. The mean parasite clearance time was significantly longer in patients treated with chloroquine plus sulfadoxine-pyrimethamine (2.9 days; 95% confidence interval [CI], 2.8-3.0 days) than in those treated with artesunate plus mefloquine (2.07 days; 95% CI, 2.0-2.1 days; P<.001) and artemether-lumefantrine (2.08 days; 95% CI, 2.0-2.1 days; P<.001). Cure rates with artemether-lumefantrine were high despite low mean daily dietary fat intake (13.8 g; 95% CI, 12.5-15.1 g) and day 7 plasma lumefantrine concentrations (0.47 mu g/mL; 95% CI, 0.38-0.56 mu g/mL). CONCLUSION: Oral artesunate plus mefloquine and artemether-lumefantrine are highly effective for the treatment of uncomplicated falciparum malaria in Laos.

Ashley, E.A., S. Krudsood, L. Phaiphun, S. Srivilairit, R. McGready, W. Leowattana, R. Hutagalung, P. Wilairatana, A. Brockman, S. Looareesuwan, F. Nosten, and N.J. White, Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. J Infect Dis, 2004. 190(10): p. 1773-82.Pubmed
Background. Dihydroartemisinin-piperaquine (DP) is a new and relatively inexpensive artemisinin-containing fixed-combination antimalarial treatment. An adult treatment course contained 6.4 mg/kg dihydroartemisinin (DHA), which is >40% lower than the level in most artemisinin-containing combinations. This raised the possibility that the efficacy of the current coformulation may not be optimal in the treatment of multidrug-resistant falciparum malaria.Methods. In 2 large randomized, controlled studies in Thailand, the recommended dose of DP was compared with a regimen with additional artemisinin derivative (12 mg/kg; DP+) and with mefloquine plus artesunate (MAS3).Results. A total of 731 patients were included: 201 in a hospital-based study and 530 in a community study. Day-28 cure rates in the hospital-based study were 100% (95% confidence interval [CI], 93.9%-100%) in the MAS3 and DP+ groups and 98.3% (95% CI, 91%-99.7%) in the DP group, with a single recrudescence on day 21. In the community study, polymerase chain reaction genotyping-adjusted cure rates on day 63 were 96.1% (95% CI, 92.6%-99.7%) in the DP group, 98.3% (95% CI, 96.1%-100%) in the DP+ group, and 94.9% (95% CI, 91.2%-98.6%) in the MAS3 group (P=.2). Adverse events were few, with an excess of mild abdominal pain in the DP group.Conclusions. The current dosage of DP (6.4 mg/kg DHA and 51.2 mg/kg piperaquine phosphate) given over the course of 48 h is highly effective, safe, and well tolerated for the treatment of multidrug-resistant falciparum malaria, and its efficacy is not improved by the addition of more DHA.

Stepniewska, K., W.R. Taylor, M. Mayxay, R. Price, F. Smithuis, J.P. Guthmann, K. Barnes, H.Y. Myint, M. Adjuik, P. Olliaro, S. Pukrittayakamee, S. Looareesuwan, T.T. Hien, J. Farrar, F. Nosten, N.P. Day, and N.J. White, In Vivo Assessment of Drug Efficacy against Plasmodium falciparum Malaria: Duration of Follow-Up. Antimicrob Agents Chemother, 2004. 48(11): p. 4271-80.Pubmed
To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r(2) = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.

Dondorp, A.M., P.N. Newton, M. Mayxay, W. Van Damme, F.M. Smithuis, S. Yeung, A. Petit, A.J. Lynam, A. Johnson, T.T. Hien, R. McGready, J.J. Farrar, S. Looareesuwan, N.P. Day, M.D. Green, and N.J. White, Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials. Trop Med Int Health, 2004. 9(12): p. 1241-6.Pubmed
OBJECTIVE: To assess the prevalence of counterfeit antimalarial drugs in Southeast (SE) Asia. DESIGN: Cross-sectional survey. SETTING: Pharmacies and shops selling antimalarial drugs in Myanmar (Burma), Lao PDR, Vietnam, Cambodia and Thailand. MAIN OUTCOME MEASURES: Proportion of artemisinin derivatives or mefloquine containing drugs of substandard quality. RESULTS: Of the 188 tablet packs purchased which were labelled as 'artesunate' 53% did not contain any artesunate. All counterfeit artesunate tablets were labelled as manufactured by 'Guilin Pharma', and refinements of the fake blisterpacks made them often hard to distinguish from their genuine counterparts. No other artemisinin derivatives were found to be counterfeited. Of the 44 mefloquine samples, 9% contained <10% of the expected amount of active ingredient. CONCLUSIONS: An alarmingly high proportion of antimalarial drugs bought in pharmacies and shops in mainland SE Asia are counterfeit, and the problem has increased significantly compared with our previous survey in 1999-2000. This is a serious threat to public health in the region.

Kumkhaek, C., K. Phra-ek, P. Singhasivanon, S. Looareesuwan, C. Hirunpetcharat, A. Brockman, A.C. Gruner, N. Lebrun, L. Renia, F. Nosten, G. Snounou, and S. Khusmith, A survey of the Th2R and Th3R allelic variants in the circumsporozoite protein gene of P. falciparum parasites from western Thailand. Southeast Asian J Trop Med Public Health, 2004. 35(2): p. 281-7.Pubmed
Allelic variation in the Plasmodium falciparum circumsporozoite protein (CS) gene has been determined by sequencing the immunodominant T-cell epitopes, Th2R and Th3R, from 95 isolates from two malaria-endemic areas in the west of Thailand. Comparison with a reference sequence revealed only non-synonymous point mutations in the two epitope regions. Point mutations were found outside these epitopes in a minority of samples, and all but four were also non-synonymous. A relatively high number of variants, 11 Th2R and 9 Th3R, were detected and comprised some that had not been previously observed. However, the Th2R*05 and the Th3R*01 allelic variants predominated, as they were found in more than 70% of the 101 sequences obtained.

Adjuik, M., A. Babiker, P. Garner, P. Olliaro, W. Taylor, and N. White, Artesunate combinations for treatment of malaria: meta-analysis. The Lancet, 2004. 363(9402): p. 9-17.Pubmed
Background Addition of artemisinin derivatives to existing drug regimens for malaria could reduce treatment failure and transmission potential. We assessed the evidence for this hypothesis from randomised controlled trials.Methods We undertook a meta-analysis of individual patients' data from 16 randomised trials (n=5948) that studied the effects of the addition of artesunate to standard treatment of Plasmodium falciparum malaria. We estimated odds ratios (OR) of parasitological failure at days 14 and 28 (artesunate combination compared with standard treatment) and calculated combined summary ORs across trials using standard methods.Findings For all trials combined, parasitological failure was lower with 3 days of artesunate at day 14 (OR 0.20, 95% CI 0.17-0.25, N=4504) and at day 28 (excluding new infections, 0.23, 0.19-0.28, N=2908; including re-infections, 0.30, 0.26-0.35, N=4332). Parasite clearance was significantly faster (rate ratio 1.98, 95% CI 1.85-2.12, N=3517) with artesunate. In participants with no gametocytes at baseline, artesunate reduced gametocyte count on day 7 (OR 0.11, 95% CI 0.09-0.15, N=2734), with larger effects at days 14 and 28. Adding artesunate for 1 day (six trials) was associated with fewer failures by day 14 (0.61, 0.48-0.77, N=1980) and day 28 (adjusted to exclude new infections 0.68, 0.53-0.89, N=1205; unadjusted including reinfections 0.77, 0.63-0.95, N=1958). In these trials, gametocytes were reduced by day 7 (in participants with no gametocytes at baseline 0.11, 0.09-0.15, N=2734). The occurrence of serious adverse events did not differ significantly between artesunate and placebo.Interpretation The addition of 3 days of artesunate to standard antimalarial treatments substantially reduce treatment failure, recrudescence, and gametocyte carriage.

Nosten, F., S.J. Rogerson, J.G. Beeson, R. McGready, T.K. Mutabingwa, and B. Brabin, Malaria in pregnancy and the endemicity spectrum: what can we learn? Trends in Parasitology, 2004. 20(9): p. 425-432.Pubmed
The increased susceptibility of pregnant women to malaria infection has long been recognized, but the magnitude of the disease burden in this particular group, together with the pathophysiology of maternal malaria and the specific difficulties in treatment, have only recently been the focus of research. Most research on maternal malaria has derived from sub-Saharan Africa where transmission is high, whereas most of the studies on the treatment of malaria and the effect of non-falciparum species has been conducted in low-transmission areas of Asia. In this paper, we attempt to improve our understanding of the disease and its mechanisms from observed differences and similarities between contrasting areas of transmission, and to identify priorities for future research.

McGready, R., E.A. Ashley, and F. Nosten, Malaria and the pregnant traveller. Travel Medicine and Infectious Disease, 2004. 2(3-4): p. 127-142.Pubmed
Malaria in pregnancy contributes to significant maternal and foetal mortality and morbidity in women in the tropics. Adverse effects for non-immune travellers are potentially devastating for mother and foetus. Women travellers should always be strongly advised against visiting malarious areas if they are pregnant or intend to get pregnant. Chemoprophylactic and treatment options for pregnant women (or those planning to conceive) are extremely limited and lag behind what can currently be offered to non-pregnant travellers. This is because of spread of multi-resistant strains of P. falciparum. Personal protection from malaria vectors remains essential. Mosquito-net and skin repellents (DEET (20%)) are effective. Diagnosis of malaria in travellers is difficult and is more likely to be missed in pregnant travellers due to lower parasitaemia. Pregnant women can succumb rapidly to severe malaria. Should the returned traveller survive an episode of malaria in pregnancy and go on to deliver, the adverse effects on the infant are potentially irreversible. These risks need to be clearly communicated.

Roper, C., R. Pearce, S. Nair, B. Sharp, F. Nosten, and T. Anderson, Stopping the Spread of Drug-Resistant Malaria. Science, 2004. 306(5704): p. 2039-40.Pubmed

Roper, C., R. Pearce, S. Nair, B. Sharp, F. Nosten, and T. Anderson, Intercontinental Spread of Pyrimethamine-Resistant Malaria. Science, 2004. 305(5687): p. 1124-.Pubmed
Here we present molecular evidence demonstrating that malaria parasites bearing high-level pyrimethamine resistance originally arrived in Africa from southeast Asia. The resistance alleles carried by these migrants are now spreading across Africa at an alarming rate, signaling the end of affordable malaria treatment and presenting sub-Saharan Africa with a public health crisis.