Prevalence of HIV drug resistance among adolescents receiving ART in Cameroon with low- or high-level viraemia.

OBJECTIVES: To characterize HIV drug resistance (HIVDR) below and above the WHO threshold of 1000 copies/mL, considered for the definition of HIV ART failure in resource-limited settings. METHODS: From a cohort of 280 adolescents (aged 10-19 years) receiving ART for at least 6 months, genotypic resistance testing (GRT) was attempted for two groups of participants: participants with low-level viraemia [LLV; viral load (VL) 200-999 copies/mL] and those in virological failure (VF; confirmed VL ≥1000 copies/mL) using an in-house method. The Stanford HIValg Program was used to identify relevant HIVDR mutations and predict the efficacy of the newly introduced tenofovir-lamivudine-dolutegravir combination. RESULTS: GRT was successfully performed in 54/58 (93.1%) eligible participants, of which 28/31 (90.3%) were in VF and 26/27 (96.3%) had LLV. A high level of resistance was found both in adolescents with LLV and those in VF, with respectively 84.6% (22/26) and 75.0% (21/28) of participants harbouring at least one HIVDR mutation. NRTIs and NNRTIs were the most affected drug classes in both population groups. In contrast, PIs were not significantly affected and dolutegravir was expected to be active for all participants tested. However, for the newly introduced dolutegravir-based combination, functional monotherapy (dolutegravir only) was potentially possible for 22.7% (5/22) of the participants with LLV. CONCLUSIONS: Our findings show that the 1000 copies/mL threshold is not an indicator of virological success and we call for a revision of the current WHO definition of VF in resource-limited countries.

Effect of sulfadoxine-pyrimethamine chemoprophylaxis in pregnant women on selection of the new P. falciparum dhps quintuple mutant carrying the I431V mutation.

BACKGROUND: A new mutation in the Plasmodium falciparum dihydropteroate synthetase gene (pfdhps), I431V, has been identified in several countries of Central and West Africa. This mutation is mostly found in association with four other SNPs on pfdhps (S436A, A437G, A581G and A613S), forming a quintuple mutant (vagKgs) and almost always associated with the Plasmodium falciparum dihydrofolate reductase gene (pfdhfr) CirnI (C50R, N51I, S108N) triple mutant. To date, nothing is known about the impact of this new pfdhps genotype on sulfadoxine-pyrimethamine (SP) resistance. OBJECTIVES: We sought to assess the prevalence of this pfdhps vagKgs quintuple mutant in two groups of pregnant women with malaria, one that took intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) and one that did not. METHODS: The pfdhfr and pfdhps genes from Plasmodium falciparum isolates collected in Yaoundé (Cameroon) from pregnant women with symptomatic malaria under IPTp-SP or not, were sequenced. RESULTS: Of 159 patients evaluated, 70 had already taken SP during pregnancy and 89 had never taken SP. Only the vagKgs allele was significantly overrepresented in the SP+ group (21.4% versus 3.4%; P < 0.001), whereas the ISgKAA mutant, widely distributed in this area and known to be less susceptible to SP, tended to be less abundant in this group (48.6% versus 64.0%; P = 0.0503). CONCLUSIONS: We found a strong overrepresentation of the CirnI/vagKgs haplotype in the IPTp-SP pregnant group, suggesting a high level of resistance of this mutant to SP. This could compromise not only the effectiveness of IPTp-SP but also the seasonal malaria chemoprevention of young children, now widely implemented.

High Prevalence of Asymptomatic Malarial Anemia and Association with Early Conversion from Asymptomatic to Symptomatic Infection in a Plasmodium falciparum Hyperendemic Setting in Cameroon.

Asymptomatic malarial parasitemia is highly prevalent in Plasmodium falciparum endemic areas and often associated with increased prevalence of mild to moderate anemia. The aim of this study was to assess the prevalence of anemia during asymptomatic malaria parasitemia and its interplay with persistent infection in highly exposed individuals. A household-based longitudinal survey was undertaken in a malaria hyperendemic area in Cameroon using multiplex nested polymerase chain reaction to detect plasmodial infections. Residents with P. falciparum asymptomatic parasitemia were monitored over a 3-week period with the aid of structured questionnaires and weekly measurements of axillary temperatures. Of the 353 individuals included (median age: 26 years, range 2-86 years, male/female sex ratio 0.9), 328 (92.9%) were positive for malaria parasitemia of whom 266 (81.1%) were asymptomatic carriers. The prevalence of anemia in the study population was 38.6%, of which 69.2% were asymptomatic. Multivariate analyses identified high parasitemia (> 327 parasites/µL) and female gender as associated risk factors of asymptomatic malarial anemia in the population. Furthermore, risk analyses revealed female gender and anemia at the time of enrolment as key predictors of early development of febrile illness (< 3 weeks post enrolment) among the asymptomatic individuals. Together, the data reveal an extremely high prevalence of asymptomatic malaria parasitemia and anemia in the study area, unveiling for the first time the association of asymptomatic malarial anemia with early clinical conversion from asymptomatic to symptomatic infection. Furthermore, these findings underscore the negative impact of asymptomatic malaria parasitemia on individual health, necessitating the development of appropriate control and preventive measures.

Immunoglobulin response to the low polymorphic Pf113 antigen in children from Lastoursville, South-East of Gabon.

Pf113 is a P. falciparum putatively GPI-anchored protein that has been so far localized at the surface of merozoites, suggesting it could interact with RBC surface during merozoite invasion. Previous studies conducted in Papua New Guinea and in Kenya have revealed that this protein is recognized by natural antibodies in individuals living in malaria-endemic areas and is associated with protective immunity in malaria, further supporting the potential of Pf113 for the development of anti-malaria vaccines. However, in Central Africa, no study on the immunogenicity of this protein has been conducted. Here, we report the characterization of the Pf113 immune response in 103 children by Enzyme-Linked Immunoabsorbent Assay (ELISA), using a recombinant form of Pf113 expressed in Escherichia coli, together with the study of the Pf113 polymorphism, after amplification and sequencing of 40 field isolates. Data showed that almost 51% of the studied individuals had positive antibody responses to the recombinant Pf113 protein, and that IgG subclass response was dominated by IgG3 (84%) followed by IgG1 (50%). Surprisingly the prevalence of IgG4 was 92%. In addition, gene analysis in field isolates from this region indicated that Pf113 was not highly polymorphic, in particular regarding high-activity binding peptides (HABPs). Our data reinforce the idea that Pf113 may be considered for inclusion in multicomponent blood-stage vaccines.

Circulating markers of oxidative stress and liver fibrosis in Sudanese subjects at risk of schistosomiasis and hepatitis.

Epidemiological studies in the developing world are frequently biased by the simultaneous presence of several infectious pathogens. In the present study, we examined the usefulness of circulating markers of oxidative stress and liver fibrosis to investigate the distinct forms of chronic liver inflammations associated with schistosomiasis and viral hepatitis, respectively. The study was performed in a Sudanese population exposed to Schistosoma. Circulating hyaluronic acid (HA) was used as a marker of liver fibrosis; the severity of schistosomiasis was determined by ultrasonic examination; viral hepatitis infection was ascertained by circulating anti-hepatitis antibodies. Serum markers were examined also in Sudanese subjects not exposed to Schistosoma infection and in French control subjects. We found a drastic decrease of lycopene levels in the subjects exposed to schistosomiasis in comparison with non-exposed Sudanese and French control subjects. Retinol, alpha-tocopherol and five carotenoids were unchanged. Lycopene depletion was unlikely to be due to variations of nutritional origin, since the lycopene/beta-carotene ratio was five-fold lower in the population at risk of schistosomiasis than in the other groups. We found that high HA serum levels were associated with severe periportal fibrosis but not with viral infection. Conversely, levels of the oxidized lipid malondialdehyde (MDA) were associated with viral infection but not with the severity of schistosomiasis, even though the two infections had additive effects. We concluded that serum markers are valuable tools for investigating the complex effects of co-existing factors of chronic liver inflammation.

Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis.

Immunity against schistosomes includes anti-infection immunity, which is mainly active against invading larvae in the skin, and anti-disease immunity, which controls abnormal fibrosis in tissues invaded by schistosome eggs. Anti-infection immunity is T-helper 2 (Th2) cell-dependent and is controlled by a major genetic locus that is located near the Th2 cytokine locus on chromosome 5q31-q33. Mutations in the gene encoding interleukin (IL)-13 that decrease or increase IL-13 production account, at least in part, for that genetic control. In contrast, protection against hepatic fibrosis is dependent on interferon (IFN)-gamma and is controlled by a major genetic locus that is located on 6q23, near the gene encoding the IFN-gamma receptor beta chain. Mutations that modulate IFN-gamma gene transcription are associated with different susceptibility to disease. These data indicate that IL-13 in the skin and IFN-gamma in the liver are key players in protective immunity against schistosomes. These roles relate to the high anti-fibrogenic activities of IFN-gamma and to the unique ability of IL-13 in Th2 priming in the skin and in the mobilization of eosinophils in tissues. The coexistence of strong IFN-gamma and IL-13-mediated immune responses in the same subject may involve the compartmentalization of the anti-schistosome immune response between the skin and the liver.