James G Kublin

Reemergence of Chloroquine-Sensitive Plasmodium falciparum Malaria after Cessation of Chloroquine Use in Malawi

In 1993, Malawi became the first African country to replace chloroquine with sulfadoxine-pyrimethamine nationwide in response to high rates of chloroquine-resistant falciparum malaria. To determine whether withdrawal of chloroquine can lead to the reemergence of chloroquine sensitivity, the prevalence of the pfcrt 76T molecular marker for chloroquine-resistant Plasmodium falciparum malaria was retrospectively measured in Blantyre, Malawi. The prevalence of the chloroquine-resistant pfcrt genotype decreased from 85% in 1992 to 13% in 2000. In 2001, chloroquine cleared 100% of 63 asymptomatic P. falciparum infections, no isolates were resistant to chloroquine in vitro, and no infections with the chloroquine-resistant pfcrt genotype were detected. A concerted national effort to withdraw chloroquine from use has been followed by a return of chloroquine-sensitive falciparum malaria in Malawi. The reintroduction of chloroquine, ideally in combination with another antimalarial drug, should be considered in areas where chloroquine resistance has declined and safe and affordable alternatives remain unavailable.

Pyrimethamine–sulfadoxine resistance in Plasmodium falciparum: what next?

Chemotherapy remains the only practicable tool to control falciparum malaria in sub-Saharan Africa, where >90% of the worlds burden of malaria mortality and morbidity occurs. Resistance is rapidly eroding the efficacy of chloroquine, and the combination pyrimethamine-sulfadoxine is the most commonly chosen alternative. Resistant populations of Plasmodium falciparum were selected extremely rapidly in Southeast Asia and South America. If this happens in sub-Saharan Africa, it will be a public health disaster because no inexpensive alternative is currently available. This article reviews the molecular mechanisms of this resistance and discusses how to extend the therapeutic life of antifolate drugs.

Effect of Plasmodium falciparum malaria on concentration of HIV-1-RNA in the blood of adults in rural Malawi: a prospective cohort study

BACKGROUND Raised HIV viral load in blood has been associated with accelerated disease progression and increased transmission of infection. To assess the effect of Plasmodium falciparum malaria on concentrations of HIV in blood, we did a prospective cohort study in Malawi. METHODS We recruited 367 HIV-1-infected adults. Among 334 people aparasitaemic at baseline, 148 had at least one malaria episode during follow-up and received antimalarial treatment. Of these, 77 had HIV-1-RNA measurements at baseline, during malaria, and post-malaria. We used linear regression with generalised estimating equations to assess effect of four definitions of malaria (any parasitaemia, parasite density > or =2000/microL, febrile parasitaemia, and febrile parasitaemia with parasite density > or =2000/microl) on changes in log HIV-1 RNA, overall and by baseline CD4 count. FINDINGS With malaria defined as any parasitaemia, HIV-1-RNA concentration almost doubled between baseline (median 96215 copies per mL) and malaria (168901 copies per mL), a 0.25 (95% CI 0.11-0.39) log increase in mean RNA concentration. HIV-1-RNA concentration fell to median 82058 copies per mL by about 8-9 weeks post-malaria. Increases in HIV-1-RNA were greatest for people with fever, parasite density 2000/microL or greater, and CD4 count more than 300 cells per muL, in whom concentrations rose from median 38483 copies per mL at baseline to 196098 copies per mL during malaria, a mean log increase of 0.82 (95% CI 0.55-1.10, p<0.0001), and fell to median 75331 copies per mL post-malaria. People who remained aparasitaemic showed no changes in HIV-1-RNA concentration. INTERPRETATION HIV-infected individuals with malaria have a significantly increased viral load, which might enhance HIV transmission and accelerate disease progression.

Plasmodium falciparum crossresistance between trimethoprim and pyrimethamine

Trimethoprim-sulfamethoxazole has been recommended as part of the standard package of care for people with HIV and AIDS in Africa. A similar antifolate combination, sulfadoxine-pyrimethamine, is now the first-line antimalarial drug in several of the African countries with the highest rates of HIV infection. We present evidence of Plasmodium falciparum cross-resistance between trimethoprim and pyrimethamine at the molecular level. The impact of trimethoprim-sulfamethoxazole on the efficacy of sulfadoxine-pyrimethamine needs to be assessed urgently, and alternative antimalarial treatment should be considered for people on trimethoprim-sulfamethoxazole prophylaxis.

Effects of HIV-1 Serostatus, HIV-1 RNA Concentration, and CD4 Cell Count on the Incidence of Malaria Infection in a Cohort of Adults in Rural Malawi

BACKGROUND To assess the effects of human immunodeficiency virus (HIV) infection on susceptibility to malaria, we compared the incidence rates of malaria by HIV type 1 (HIV-1) serostatus, baseline blood HIV-1 RNA concentration, and baseline CD4 cell count, over the course of a malaria season. METHODS We followed a cohort of 349 adults in Malawi. For the 224 HIV-1-seropositive adults (64% of the cohort), we measured HIV-1 RNA concentration (n=187) and CD4 cell count (n=184) at baseline. Parasitemia was defined as presence of asexual parasites on a thick film of blood and was treated with sulfadoxine/pyrimethamine (SP), in accordance with national policy. Hazard ratios (HRs) of parasitemia were estimated using Cox regression. Demographics were adjusted for. RESULTS HIV-1 seropositivity was associated with parasitemia (adjusted HR, 1.8 [95% confidence interval {CI}, 1.2-2.7] for a first parasitemia episode; adjusted HR, 2.5 [95% CI, 1.5-4.2] for a second parasitemia episode [> 14 days after the first episode]; adjusted HR, 1.9 [95% CI, 1.4-2.6] for parasitemia overall). Treatment failure (parasitemia < or = 14 days after SP treatment) did not differ by HIV-1 serostatus (risk ratio, 1.3 [95% CI, 0.5-3.2]). HIV-1 RNA concentrations and CD4 cell counts were moderately but inconsistently associated with parasitemia. A high parasite density with fever was associated with HIV-1 seropositivity and low CD4 cell count. CONCLUSION HIV-infected adults in malaria-endemic areas are at increased risk for malaria. Where possible, additional malaria prevention efforts should be targeted at this population.

Comparison of chlorproguanil-dapsone with sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in young African children: double-blind randomised controlled trial

BACKGROUND Increasing resistance to sulfadoxine-pyrimethamine is leading to a decline in its effectiveness. We aimed to assess the safety profile of chlorproguanil-dapsone (CD), and to compare the safety and efficacy of this drug with that of sulfadoxine-pyrimethamine (SP) as treatment for uncomplicated falciparum malaria. METHODS We undertook a double-blind, randomised trial in 1850 consecutively recruited children with uncomplicated falciparum malaria, pooling data from five African countries. Analyses were based on all randomised patients with available data. FINDINGS CD was significantly more efficacious than SP (odds ratio 3.1 [95% CI 2.0-4.8]); 1313 patients (96%) given CD and 306 (89%) given SP achieved acceptable clinical and parasitological response by day 14. Adverse events were reported in 46% and 50% of patients randomised to CD and SP, respectively (treatment difference -4.4%, [95% CI -10.1 to 1.3]). Haemoglobin in the CD group was significantly lower than in the SP group at day 7, a difference of -4 g/L (95% CI -6 to -2). Mean day 14 haemoglobin (measured only for the small number of patients whose day 7 data caused concern) was 94 g/L (92-96) and 97 g/L (92-102) after CD and SP, respectively. Glucose-6-phosphate dehydrogenase deficient patients on CD had greater odds than those on SP of having a fall of 20 g/dL or more in haemoglobin when baseline temperature was high. Methaemoglobinaemia was seen in the CD group (n=320, mean 0.4% [95% CI 0.4-0.4]) before treatment, 4.2% (95% CI 3.8-4.6) (n=301) at day 3, and 0.6% (0.6-0.7) (n=300) at day 7). INTERPRETATION CD had greater efficacy than SP in Africa and was well tolerated. Haematological adverse effects were more common with CD than with SP and were reversible. CD is a useful alternative where SP is failing due to resistance.

P. falciparum dihydrofolate reductase and dihydropteroate synthase mutations: epidemiology and role in clinical resistance to antifolates

Plasmodium falciparum resistance to the antifolates has arisen rapidly in Asia and South America, and threatens the usefulness of these drugs in Africa. In vitro resistance to the antifolates is determined by mutations in parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). The role of DHFR and DHPS mutations in therapeutic failure of antifolate antimalarials is less clear. This review summarizes molecular epidemiological surveys, studies of in vivo selection of mutant alleles by drug treatment, and prospective studies of the ability of mutation-specific assays to predict clinical outcomes, and discusses the potential use of these assays for surveillance of resistance.

Molecular assays for surveillance of antifolate-resistant malaria

to detect all known DHFR and DHPSmutations, and correlations were determined betweenDHFR and DHPS genotypes and therapeutic responsedefined as sensitive (S), RI, RII, or RIII resistance.A genotype defined by DHFR mutations Asn-108, Ile-51,and Leu-164 combined with DHPS mutations Gly-437,Glu-540, and Gly-581 was detected in 7/8 cases (87·5%) ofRIII resistance, 9/13 cases (69·2%) of RII resistance, 5/13cases (38·5%) of RI resistance, and 0/11 sensitive cases(0·0%) (figure). The Bolivia repeat mutation at codon 30,

Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study

Abstract Objective To measure the efficacy of sulfadoxine-pyrimethamine treatment of falciparum malaria in Malawi from 1998 to 2002, after a change from chloroquine to sulfadoxine-pyrimethamine as first line treatment in that country in 1993. Design Prospective open label drug efficacy study. Setting Health centre in large peri-urban township adjacent to Blantyre, Malawi. Participants People presenting to a health centre with uncomplicated Plasmodium falciparum malaria. Main outcome measures Therapeutic efficacy and parasitological resistance to standard sulfadoxine-pyrimethamine treatment at 14 days and 28 days of follow up. Results Therapeutic efficacy remained stable, with adequate clinical response rates of 80% or higher throughout the five years of the study. Analysis of follow up to 28 days showed modest but significant trends towards diminishing clinical and parasitological efficacy over time within the study period. Conclusion Contrary to expectations, sulfadoxine-pyrimethamine has retained good efficacy after 10 years as the first line antimalarial drug in Malawi. African countries with very low chloroquine efficacy, high sulfadoxine-pyrimethamine efficacy, and no other immediately available alternatives may benefit from interim use of sulfadoxine-pyrimethamine while awaiting implementation of combination antimalarial treatments.

A prospective study of bloodstream infections as cause of fever in Malawi: clinical predictors and implications for management

Objective  To determine the contribution of a blood culture service to the diagnosis of fever in a resource‐poor setting and to identify clinical predictors of specific bloodstream infections (BSI).