Phan Trong Giao

Pharmacokinetic Interactions of Antimalarial Agents

Combination of antimalarial agents has been introduced as a response to widespread drug resistance. The higher number of mutations required to express complete resistance against combinations may retard the further development of resistance. Combination of drugs, especially with the artemisinin drugs, may also offer complete and rapid eradication of the parasite load in symptomatic patients and thus reduce the chance of survival of resistant strains.The advantages of combination therapy should be balanced against the increased chance of drug interactions. During the last decade, much of the pharmacokinetics and metabolic pathways of antimalarial drugs have been elucidated, including the role of the cytochrome P450 (CYP) enzyme complex. Change in protein binding is not a significant cause of interactions between antimalarial agents. CYP3A4 and CYP2C19 are frequently involved in the metabolism of antimalarial agents. Quinidine is a potent inhibitor of CYP2D6, but it appears that this enzyme does not mediate the metabolism of any other antimalarial agent. The new combinations proguanil-atovaquone and chlorproguanil-dapsone do not show significant interactions.CYP2B6 and CYP3A4 are involved in the metabolism of artemisinin and derivatives, but further studies may reveal involvement of more enzymes. Artemisinin may induce CYP2C19. Several artemisinin drugs suffer from autoinduction of the first-pass effect, resulting in a decline of bioavailability after repeated doses. The mechanism of this effect is not yet clear, but induction by other agents cannot be excluded. The combination of artemisinin drugs with mefloquine and the fixed combination artemether-lumefantrine have been studied widely, and no significant drug interactions have been found. The artemisinin drugs will be used at an increasing rate, particularly in combination with other agents. Although clinical studies have so far not shown any significant interactions, drug interactions should be given appropriate attention when other combinations are used.

Seroprevalence of dengue antibodies, annual incidence and risk factors among children in southern Vietnam

Dengue is highly endemic in southern Vietnam and all four serotypes of dengue virus have already been identified. To determine the age‐specific prevalence of dengue and associated risk factors, we conducted a serological study at two primary schools and assessed risk factors by analysing childrens questionnaires and household surveys. Sera were collected from 961 primary schoolchildren in Binh Thuan Province and tested for the presence of dengue virus serum antibodies using an indirect immunoglobulin G (IgG) enzyme‐linked immunosorbent assay (ELISA). The antibody prevalence of the total population was 65.7% (n = 631) which increased from 53.0 to 88.2% with age. The annual incidence of a first dengue infection, estimated by binary regression of the seroprevalence by age, was 11.7%. Interestingly, the prevalence of dengue IgG antibodies was significantly higher in children who confirmed using a pit latrine (RR 1.467, 95% CI: 1.245–1.730) and whose domestic environment contained discarded cans (RR 1.238, 95% CI: 1.042–1.470) and pigs (RR 1.228, 95% CI: 1.002–1.504). The epidemiology of dengue in southern Vietnam is stable with a constantly high annual incidence of first infections. Transmission occurs mainly peri‐domestically, which has important public health implications.

Dengue as a cause of acute undifferentiated fever in Vietnam

BackgroundDengue is a common cause of fever in the tropics but its contribution to the total burden of febrile illnesses that is presented to primary health facilities in endemic regions such as Vietnam, is largely unknown. We aimed to report the frequency of dengue as a cause of fever in Binh Thuan Province, to describe the characteristics of dengue patients, and analyze the diagnostic accuracy of the health care workers and the determinants of the diagnostic process.MethodsAll patients presenting with acute undifferentiated fever at twelve community health posts and one clinic at the provincial malaria station, Binh Thuan Province, a dengue endemic province in southern Vietnam, were included. Record forms were used to fill in patient and diseases characteristics, pre-referral treatment, signs and symptoms, provisional diagnosis and prescribed treatment, referral and final outcome. Serum samples were collected at first presentation and after 3 weeks for serologic diagnosis.Results2096 patients were included from April 2001 to March 2002. All 697 patients with paired serum samples were tested for dengue virus IgM and IgG. Acute dengue was found in 33.6% cases and past dengue virus infections were found in 57.1% cases. Acute primary infections were more common among children under 15 years old than among adults (7.7% vs. 3.5%, p value < 0.001). Younger age significantly predicted acute dengue (RR per increasing year of age (95 % CI): 0.986 (0.975–0.997, p value = 0.014). 48.9% of cases with clinical diagnosis of acute dengue were serologically confirmed and 32.5% of cases without clinical diagnosis of acute dengue were positive by serology after all (OR = 1.981, p value 0.025, 95% CI: 1.079 – 3.635). Tourniquet test was not a predictor for dengue diagnosis.ConclusionDengue is responsible for one third of the fevers presented to the public primary health services in Binh Thuan, southern Vietnam. It presents as a highly unspecific illness and is hardly recognized as a clinical entity by primary physicians.

CV8 a new combination of dihydroartemisinin piperaquine trimethoprim and primaquine compared with atovaquone-proguanil against falciparum malaria in Vietnam.

Objectives  To study a new combination, based on dihydroartemisinin and piperaquine (CV8) and atovaquone/proguanil (Malarone) for treatment of uncomplicated falciparum malaria in Vietnam.

Seroepidemiology of leptospirosis in southern Vietnamese children.

Objective  To estimate the seroprevalence of human leptospirosis in southern Vietnam.

Early diagnosis and treatment of uncomplicated malaria and patterns of health seeking in Vietnam

Early diagnosis and treatment of malaria (EDTM) is a key component of malaria control. The success of EDTM depends on health seeking behaviour and the quality of the health service. This study assessed self‐diagnosis, treatment and treatment delay after the introduction of EDTM in 1993. In southern Vietnam EDTM comprises microscopic diagnosis and free treatment with artemisinin derivatives at public health facilities. Until 2001, 1698 questionnaires had been completed by patients participating in randomized treatment trials of uncomplicated malaria. The presumptive self diagnosis ‘malaria’ increased from 68% in 1993 to 100% in 2001 and self‐treatment decreased, from 74% to 8% in 2000 and 24% in 2001. The median (maximum) delay between first symptoms and seeking treatment at a public health facility decreased from 3 (23) to 1.3 (3) days (P < 0.001) Concomitant was a significant decline of reported incidence of malaria‐associated mortality, severe malaria and uncomplicated malaria. If offered an attractive package of EDTM, patients become sensitized to the possibility of malaria and less likely to self‐treat. EDTM should be provided as soon as possible to all symptomatic patients, aiming at reducing treatment delay to a maximum of 2 days.

Evaluation of Two Rapid Immunochromatographic Assays for Diagnosis of Dengue among Vietnamese Febrile Patients

ABSTRACT Results from two dengue rapid tests, the PanBio Duo cassette and the SD Bioline strip test, were compared to those of enzyme-linked immunosorbent assays (Focus Diagnostics) from sera of 200 Vietnamese febrile patients. The PanBio assay was superior, with sensitivity and specificity values for acute-phase serum samples of 54% and 70% (immunoglobulin M) and 70% and 88% (immunoglobulin G), respectively.

Detection of dengue nonstructural 1 (NS1) protein in Vietnamese patients with fever

Diagnosing dengue in febrile patients is challenging. Of a total of 459 patients with acute undifferentiated fever, randomly selected from 12 primary health facilities and 1 clinic of the provincial malaria station in southern Vietnam, dengue-specific antibody (Ab) and NS1Ag enzyme-linked immunosorbent assay (ELISA) (Platelia, Bio-Rad Laboratories, Hercules, CA 94547, US) were performed on acute (t0) and convalescent (t3 weeks) sera. Polymerase chain reaction (PCR) was used for confirmation. Based on a composite of the NS1Ag-ELISA, Ab-ELISA, and PCR results, 54 (12%) patients had acute dengue. Positive and negative predictive values were 65% and 98% for the Ab-based diagnosis and 91% and 92% for NS1Ag, respectively. The agreement between Ab- and NS1Ag-based diagnosis was poor (kappa value, 0.2). Two patients without dengue had detectable NS1Ag on t0 and t3, 1 just above the cutoff value and 1 with very high values. For 5 dengue patients, NS1Ag was still detectable at very high levels at t3. Dengue NS1Ag can be used for early diagnosis of dengue; infrequent false-positive results need further clarification.

Seroepidemiology and serological follow-up of anti-leptospiral IgG in children in Southern Vietnam

A follow-up study was conducted with 23 months interval to investigate the seroepidemiology and persistence of Leptospira IgG antibodies among healthy children in Binh Thuan province, Southern Vietnam. Sera from 262 children (7-13 years of age) were collected and analysed with a commercially available enzyme-linked immunosorbent assay (ELISA) for Leptospira IgG. Seroconversion was observed in 10.4% (22 of 211, 95% CI: 5.6-26.7) of the children, of whom 18 (8.5%) had probably and four (1.9%) had certainly been exposed to Leptospira. Based on the reduction of sero-negatives of 1.9% among children who have been certainly exposed, the annual seroconversion rate, a measure of the incidence rate of Leptospira infections, corresponds to 0.99% (95% CI: 0.39-2.52). In 61% (31 of 51, 95% CI: 47.1-73.0) of the children with past-infection, Leptospira IgG antibodies remain detectable after 2 years. Data from this study indicate that IgG antibody responses against Leptospira may persist at least for 2 years in children without manifestations of leptospirosis. Results of study uncover the true incidence of leptospirosis infection, the dynamics of waxing and waning antibody concentrations and points at a larger burden of clinically non-significant Leptospira infections in Southern Vietnam. This also indicates background reactivity for serological testing and thus serological result of a single serum sample must be carefully interpreted.

Nutritional status following malaria control in a Vietnamese ethnic minority commune.

Objective:To study whether control of malaria leads to catch-up growth or an increase of obesity in a marginally nourished population.Setting:A Vietnamese ethnic minority commune in southern Vietnam.Design:Repeated annual anthropometric surveys were performed from 1995 to 2000. Z-scores for height, weight and BMI for age and weight-for-height were determined by using NCHS 1978 and CDC 2000 reference tables and by the LMS method.Intervention:Active malaria control that reduced the parasite carrier rate from 50% in 1994 to practically nil in 1998.Results:Inhabitants were generally of short stature and very thin. Using the US reference tables, the prevalence of moderate/severe stunting among children was 53/24% and of wasting 27/9% in the first survey in 1995. Physical condition and normal daily activities of most inhabitants were normal. The repeated LMS-Z-scores uncovered a significant recovery of stunting, extending into preadolescence, including the development of a pubertal growth spurt for girls and enhancement of pubertal growth in boys, after control of malaria. The mean (95% CI) annual increase of Z-height-for-age was 0.11 (0.09–0.12) for boys and 0.14 (0.13–0.15) for girls (P<0.001). As a consequence, weight-for-age and BMI Z-scores decreased without indication of developing obesity.Conclusion:Catch-up growth, extending into preadolescent age, was observed in a Vietnamese ethnic minority population with a chronic state of low food intake, without indication of developing obesity. The control of malaria was probably the most significant contribution to this catch-up growth.