Deayton, Jane Robyn; (2002) Natural history of cytomegalovirus disease in the era of highly active antiretroviral therapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis examines changes in the natural history of CMV infection in the HIV-infected population following the introduction of HAART. The incidence of CMV retinitis declined dramatically and survival following retinitis improved significantly; the results of this thesis show that this is predominantly due to HAART. Importantly, an increased CD4 count following HAART was protective against the development of retinitis even in patients previously at high risk. Discontinuation of maintenance therapy for CMV after successful HAART was safe in selected patients. However, HAART failure was associated with recurrence of CMV viraemia and a high incidence of anti-CMV drug resistance mutations. Qualitative PCR studies of CMV load after HAART demonstrated complete suppression of CMV viraemia, correlated with protection against CMV retinitis. In order to assess T-helper function following HAART, anti-CMV gB, anti-HIV Gag and anti-HIV Env antibodies were measured using an immunofluorescence assay. There was a direct relationship between inhibition of HIV replication and control of CMV replication by the reconstituting immune system as demonstrated by an increase in anti-gB titres. In contrast, there was no change in anti-Gag titres and a decrease in anti-Env titres after HAART, consistent with the requirement for ongoing HIV replication to maintain high levels of immune stimulation. Calculation of the half-life of decline of CMV viraemia following HAART showed that this was variable; these data were used to estimate the mean antiviral efficacy achieved through immune control at 63%. A prospective study of patients receiving HAART showed that the detection of CMV viraemia was associated with a significantly increased hazard of CMV disease, AIDS and death. The effect of CMV viraemia was independent of CD4 count and HIV load, showing that CMV remains important prognostically in the era of HAART. All studies conducted in this thesis gained full approval from the local Ethics Committee.

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