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Title: HIV, immune activation and endothelial damage in Malawian adults
Author: Kelly, Christine Mary
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Mortality from cardiovascular disease (CVD) is predicted to surpass that of infectious disease in sub-Saharan Africa (SSA) by 2030. HIV doubles the risk of CVD in high resource settings, but the contribution of HIV and immune activation to the risk of CVD in SSA is unknown. HIV-1-infected adults with CD4 < 100 cells/ul were recruited 2 weeks following initiation of anti-retroviral therapy (ART) within the REALITY trial (NCT01825031), along with healthy HIV-uninfected adults and followed for 44-weeks. Acute infections (malaria, TB, cryptococcal meningitis, pneumonia, gastroenteritis) were recorded. Pulse wave velocity (PWV) was assessed using the Vicorder system. Flow cytometry identified T-cell activation (HLA-DR/CD38+), exhaustion(PD1+) and senescence(CD57+) in all participants and circulating microparticles(CMPs) in 72 participants. Independent predictors of PWV were identified using linear regression. Backwards elimination was performed with an exit of p > 0.1 Variables with univariable p < 0.2 were included (spearman-rho or Wilcoxon ranksum). 279 HIV-infected adults had similar median(IQR) age [36(31-43) vs 35(3-41) years, p=0.4], but lower systolic BP [120(108-128) vs 128(114-134) mmHg, p < 0.01], BMI [20(18-21) vs 22(20-25) kg/m2, p < 0.01] and proportion of women [122(44%) vs 66(60%), p < 0.01] than 110 HIV uninfected adults. Following adjustment for confounders, HIV infection was associated with a 12%-increase in PWV (p < 0.01) at baseline, which remained at week 10 (14%-increase, p=0.02) but resolved by week 24. %CD4-PD1 and %CD8-PD1 were independently associated with PWV at baseline (fold change 2% and 3% per 10%increase, p=0.06 and 0.05 respectively). A decrease in %CD4-PD1 was associated with improvement in PWV by week 44 (rho 0.20, p=0.02). At baseline, median (IQR) CMPs were increased in HIV infection [5.1(2.0-18.0) x 10⁶ versus 0.4(0.2-6.0) x 10⁶, p < 0.00001)] and in high versus low immune activation [4.0(2.3-5.6) x 10⁶ versus 0.3(0.1-0.5) x 10⁶, p < 0.0001)]; and were strongly related to PWV (rho 0.42, p < 0.001). An acute infection during the study carried a 51% adjusted increase in %CD8 activated T cells at week 44 (p=0.02) and an increase in PWV at week 44 of 0.80m/s [versus -0.10m/s (p=0.01)] for HIV uninfected participants. These results strongly implicate HIV and immune activation in increased endothelial damage during the first 12 weeks of ART therapy. Improvement in PWV on ART and cotrimoxazole is associated with decreases in immune activation. HIV and co-infections may present modifiable CVD risk factors in low resource SSA setting.
Supervisor: Khoo, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral