Plasmodium falciparum causes the most severe form of malaria and is the most common malaria species in sub-Saharan Africa. Chloroquine used to be the most common drug for the treatment of malaria. Due to development of resistance, chloroquine is no longer efficacious in most of the world. The first line option for treatment of P. falciparum is now artemisinin based combination therapy, such as artemether-lumefantrine. In Guinea-Bissau, in contrast to the rest of Africa, chloroquine has been considered to be effective by practitioners in line with clinical trials by our group. Artemether-lumefantrine replaced chloroquine for the treatment of malaria in Guinea-Bissau in 2008. The main aim of this thesis has been to study if and why chloroquine has remained efficacious in Guinea-Bissau. We have shown that chloroquine resistance is associated with the CVIET haplotype at amino-acid positions 72-76 of the chloroquine resistance transporter (pfcrt). Genotyping and in vitro data presented in the thesis indicate that the proportion of resistant P. falciparum has been stable and low (~25%) since the early 90 s. In line with that, P. falciparum with pfcrt 76T do not accumulate during the high transmission season, in Guinea-Bissau. Concurrently, approximately 3 times standard dose chloroquine has been routinely prescribed and taken without severe adverse events. In a randomized clinical trial, we show that the PCR corrected day 28 and day 42 efficacies of double standard dose chloroquine were 95 and 94% respectively. The corresponding artemether-lumefantrine efficacies were 97%. Both antimalarial treatment options were well tolerated. The PCR corrected day 28 efficacies of double standard dose and standard dose chloroquine against P. falciparum with pfcrt 76T were 78-87% and 38%, respectively. Chloroquine concentrations were lower in children with PCR adjusted treatment failure compared to children with PCR adjusted adequate clinical and parasitological response by day 42. Recrudescent P. falciparum following treatment with artemether-lumefantrine or chloroquine appeared to carry opposite alleles at pfcrt codon 76 and multidrug resistance gene codon 86. The dose and concentration dependent efficacy of chloroquine against P. falciparum with pfcrt 76T indicate that chloroquine resistance can be overcome by higher doses of chloroquine. High total chloroquine doses are well tolerated when split into repeated smaller daily doses. The lack of seasonal accumulation of pfcrt 76T indicates that the dosage schedule commonly used in Guinea-Bissau is efficacious and that pfcrt 76T is associated with a loss of fitness. Double standard dose chloroquine and artemetherlumefantrine fulfill the WHO efficacy requirements for antimalarials about to be adopted as treatment policy.
This thesis is an investigation of the epidemiology of human virus type 2 (HIV-2) infection in two West African countries, Guinea-Bissau and The Gambia.
Chapter I discusses the setting of the studies and puts them into the perspective of previous research conducted at the Medical Research Council (MRC) Laboratories in The Gambia.
Chapter 2 is a review of the epidemiology of HIV-2, and describes the key differences of HIV-2 infection compared to HIV-1, including a lower transmission rate, a more limited geographical spread, stable or decreasing prevalence and a better prognosis.
Chapter 3 describes the results of the first round of the Gambian HIV sentinel surveillance programme in 2000-01. The HIV-1 prevalence 15 years after detection of the first case in the country, was still relatively low at 1.0%, and HIV-2 prevalence was 0.8%. In comparison to an earlier cross-sectional study among pregnant women carried out in 1993-95, this shows a reversal, as then HIV-2 was the more prevalent virus (1.1%) and HIV-1 was less common (0.6%).
Chapter 4 describes the incidence of HIV-2 in a rural area in north-west Guinea-Bissau. The incidence was 4.6 per 1000 persons per year, which is lower than expected in view of the high prevalence (8%). Among the risk factors independently associated with incident infection in women were active syphilis, history of vaginal discharge, having been divorced, living in the central part of the village, and having lived elsewhere in Guinea-Bissau. Among men age below 30 years and active syphilis were significantly associated with new infections.
Chapter 5 examines the hypothesis, put forward by researchers from Dakar and Boston, that HIV-2 infection might offer protection against subsequent infection with HIV-1. In the same rural population in Guinea-Bissau as described in Chapter 3, we found that the incidence of HIVA infections was higher among those already infected with HIV-2, so HIV-2 could possibly be a risk factor for HIV 1 acquisition, rather than a protective factor.
Chapter 6 examines the mortality in a cohort of patients attending a sexually transmitted disease clinic at the MRC facilities in Fajara. This study confirmed that the survival of HIV-2 infected patients was better than that of HIV-l infected patients. In the group of patients with normal CD4 count (< 200 cells / ul) the mortality of HIV-2 infected subjects was half of that in HIV-l infected subjects, but among those with a low CD4 count (<200 cells / ul), there was no difference in mortality between those infected with HIV-1 or HIV-2. This study also described the survival of patients who are infected with both viruses. These patients had a poor prognosis; their mortality rate was similar to those of patients with HIV-L This indicates that HIVQ is not able to mitigate the course of HIV-1 disease.
Chapter 7 compares the survival of HIV-2 infected women with that of HIV l infected and HIV-uninfected women. Unlike the study population in Chapter 6, these women were nut recruited because they were ill, but were screened for HIV at their first visit to an antenatal clinic as pan of a study examining mother-to-child transmission rates of HIV-1 and HIV-2 in 1993-5. This study population is more representative of the general population than the highly selected patients of Chapter 6. In 2001 we re-visited these women and established their vital status. The results confirmed some earlier findings: prognosis with HIVAZ infection was better than with HIV 1 infection, and the mortality rate is predicted by the plasma viral load in both infections. The surprising result was that in this seroprevalent cohort more than 50% of women with HIV-l were still alive eight years after recruitment. This indicates that the survival with HIV-1 in West African women is similar to that of women in Europe or North America prior to the use of highly active antiretroviral treatment (HAART). Another important finding was that it is not the type of virus per se that is predictive of mortality, but the plasma viral load. In other words, if a person has infection with a high plasma viral load, then the prognosis is as bad as that of a person with HIV-1 and high plasma viral load. This suggests that the start of treatment in HIV-2 disease should be guided by the same indicators as in HIV-1 disease.
Chapter 8 describes survival of eight children who were infected with HIV-2 by their mothers around the time of delivery. Perhaps surprisingly, this is the world’s largest cohort of perinatally infected children. An earlier study following up these children had found that all eight had survived to 18 months of age. After 5-7 more years three of the eight children had died. This was a significantly higher mortality rare than in an HIV uninfected control group of children, but was lower than in an infected group of children. The numbers were very small though and few conclusions can be drawn. It does suggest however, that children with perinatally acquired HIV-2 infection need the same care and prophylaxis as HIV-1 infected children.
Finally, Chapter 9 draws conclusions from these studies, and identifies outstanding research questions. It remains unclear what initiated the HIV-2 epidemic, and why if is in declinenow. The plasma viral load in HIV-2 infected people is generally lower than in HIV-l infected people, but the reasons for this are unknown. Another unresolved question is why only a limited proportion of HIV-2 infected people have a high plasma viral load and develop AIDS, and how large this proportion is. If a preventive vaccine were to be developed, very large trials would be needed to test the protective efficacy of such a vaccine, as the incidence of HIV-2 is low. HIV-2 prevalence is stable or declining in most countries, and HIV-2 is not a global threat. Nevertheless many people in West Africa with this virus will develop immunodeficiency and die from AIDS. Trials and cohort studies are needed to identify appropriate treatment.
Le but de cette thèse est l’étude des conséquences à court et long termes de la rougeole et de la vaccination contre la rougeole dans les conditions d’une zone rurale du Sénégal. Après un premier chapitre consacré aux bases méthodologiques de l’étude, la thèse décrit les facteurs de risque de la létalité de la rougeole. Elle analyse aussi la survie à long terme après la rougeole et discute les divergences des résultats rapportés sur la mortalité à long terme après la maladie morbilleuse. Dans un troisième chapitre, les effets secondaires précoces et la mortalité à long terme après la vaccination antimorbilleuse sont étudiés. Cette analyse met un accent particulier sur les vaccins à haut titre contre la rougeole administrés avant l’age de 9 mois. Les déterminants possibles des résultats inattendus observés sont aussi étudiés dans un dernier chapitre. (Résumé d’Auteur)
La mortalité des enfants en Afrique au Sud du Sahara est la plus forte du monde.
Mieux connaître les niveaux, les facteurs, les causes de cette mortalité et leurs évolutions est donc primordial, mais difficilement réalisable à cause du manque d’informations démographiques et sanitaires disponibles dans les pays africains.
D’où le recours à des observatoires de population.
L’observatoire de population de Bandafassi est situé au Sud-Est du Sénégal, en zone rurale éloignée des grands centres urbains.
Il est constitué de 38 villages où vivent 8607 habitants (au 1er mars 1994) appartenant à trois ethnies : les Bedik, les Peul et les Malinké.
Trois types d’enquêtes ont été conduites dans cette population: un recueil routinier des informations démographiques commencé en 1970 chez les Malinké, en 1975 chez les Peul et en 1980 chez les Bidet; une enquête sur les causes de décès d’enfants, par autopsies verbales auprès des mères, à partir de 1985; enfin une enquête de couverture vaccinale des enfants en 1992.
Il en ressort que la mortalité des enfants dans cette zone rurale isolée est très forte : le risque de mourir avant 5 ans sur la période 1981-1993 y est de 313 pour mille.
La rougeole, frappant les villages par épidémies meurtrières, était une des principales causes de la mortalité jusqu’en 1985.
Cependant la mortalité des enfants a baissé de moitié entre 1981 et 1993.
Link to article: Desgrées Du Loû, Annabel and Pison, Gilles. Le rôle des vaccinations dans la baisse de la mortalité des enfants au Sénégal. In: Population, 50e année, n°3, 1995 pp. 591-620.