Mortalité et activation immunitaire chronique chez les personnes vivant avec le VIH naïves de traitement antirétroviral en Afrique de l’Ouest

HIV/AIDS is a major public health problem in Sub-Saharan Africa, which accounts for 75% of the burden of HIV/AIDS in 13% of the world's population. Sub-Saharan Africa has benefitted from major advances in the fight against HIV/AIDS, including antiretroviral therapy (ART). This has helped to improve performance indicators in the fight against HIV/AIDS, although some areas such as West Africa have lagged behind. Interventions are mainly guided by the World Health Organization recommendations, which are based on evidence obtained in settings that differ from real-life in resource-limited settings (RLS). Observational data are scarce, particularly in ART-naive people living with HIV (PLHIV) with high CD4 cell counts. For example, the new recommendations for initiating ART for all PLHIV regardless of CD4 cell counts remain to be validated in RLSs. Mortality and chronic immune activation (CIA) are also two important topics in this population. CIA plays a central role in the progression of HIV as well as other factors such as viral serotype. A certain level of CIA has been reported in exposed seronegative (ESN) people such as seronegative partners in serodiscordant couples. The extent of CIA and its relationship to sexual exposure to HIV (SEHIV) has been little studied in West Africa. The same holds true for the association between CIA and smallpox vaccination (SPV) despite several studies that have reported a positive association between this vaccination and the immune system of PLHIVs. This thesis had three objectives: 1) to describe mortality in ART-naive PLHIVs with a baseline (at entry in the cohort) CD4 cell counts ≥350/μL in West Africa, and to assess its association with these CD4 cell counts, the viral serotype and the CIA level at the entry in the cohort; 2) to compare the level of CIA of ESNs with those of PLHIVs and seronegative controls and then to assess its association with SEHIV in ESNs and seronegative controls; 3) to evaluate the association between SPV and CIA in ART-naïve PLHIVs. For objective 1, a cohort study has been undertaken with competitive risk analyzes (Fine-Gray regression for competing risk) and classical survival analyzes (Kaplan Meier and Cox models) wich allow estimating respectively the sub-distribution Hazard ratio (sHR) and the Hazard ratio (HR). Two analytical cross-sectional studies have also been undertaken (for each objective 2 and 3) with logistic regression models and linear regression models. The multivariate regression models allowed estimating the adjusted relative risks using a 10% change in estimate method considering some co-variables such as age, sex, education level and inclusion period. We used beta-2-microglobulin (β2m) as soluble marker of CIA.  The cohort study (objective 1) that included 908 Gambian ART-naïve PLHIVs with CD4 cell count ≥350/μL at the entry in the cohort has found a death incidence rate of 7.5/100 person-years (95% confidence interval (95% CI)= 6.3-8.9). The risk of death was higher at CD4 cell count 350-499 compared to CD4 cell count ≥500 (adjusted HR= 1.49; 95% CI: 1.07-2.07). Compared to HIV-2, mortality was higher for HIV-1 and HIV-1+2 co-infection (adjusted HR=1.66; 95% CI: 1.26-2.81 and 2.15; 95% CI: 1.24-3.73, respectively). A high level of CIA was also associated with a higher risk of death (adjusted HR=3.23; 95% CI: 2.01-5.19 for those with a level of β2m ≥2.85 mg/L compared to those with a level <2.85 mg/L). The cross-sectional study (objective 2) comparing 54 heterosexual serodiscordant couples to 40 seronegative controls has showed that SEHIV was associated with a high (>2.2 mg/L) level of CIA (adjusted odds ratio (OR)=5.36; 95% CI: 1.20-23.88); but not with a moderate (>1.81mg/L) level of CIA (adjusted OR=2.08; 95% IC: 0.64-6.75). Finaly, for the cross-sectional study on smallpox vaccination (objectif 3) which included 101 ART-naïve PLHIVs, we did not find any association between SPV and CIA (adjusted β = -0.08; 95% CI: -0.80-0.63 for those who have been vaccinated compared to those who have not been vaccinated). The results of this thesis suggest that earlier initiation of ART could reduce mortality among PLHIVs in West Africa. Low level of CIA could also reduce mortality. However, the results do not suggest that HIV-2 infection slows HIV-1 disease progression. The results also allow us to generate hypotheses on two ESN profiles: “immunoquiescent” which could have correlates of protection against HIV infection and “immunosusceptible” whose level of CIA depends on SEHIV. Finaly, SPV would not appear to be associated with HIV progression through its impact on CIA. Our results are produced in a “real-life” context with technically and financially accessible measures in RLSs. They might be easily reproducible in the health systems of RLSs.

Keyphrases: CD4, HIV, mortality, immune activation, viral serotype, sexual exposure, serodiscordant couples, smallpox vaccination