MacRae, Eilidh (2015) The impact of a UK HIV-1 resistance database for the management and improvement of the clinical care of people living with HIV-1. Doctoral thesis, University of West London.
Eilidh MacRae PhD thesis (Final - May 2016).pdf - Draft Version
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Background: The introduction of highly active antiretroviral therapies (HAART) in 1996 to treat patients living with the human immunodeficiency virus type 1 (HIV-1), led to dramatic improvements in their mortality and morbidity. However, high levels of adherence to HAART regimens are required and due to the very nature of HIV-1: its high replicative capacity and lack of a proof reading mechanism, drug resistance mutations emerge, which impact on the ability of the drugs to suppress the patient’s circulating viruses. Genotypic resistance testing can determine whether mutations have developed which confer resistance to specific antiretrovirals (ARV) and thus enhance clinical care.
Methods: A clinical cohort database was developed to host the demographic, treatment and resistance mutation data for patients living with HIV-1 across the United Kingdom (UK) who had a genotypic resistance test (tests) conducted as part of their clinical care. These data were pooled and interrogated to determine the evolution and dynamics of resistance in targeted sub-groups of patients including treatment-naïve patients; treatment-experienced patients and their potential susceptibility to new ARV drugs; and the evolution of new subtype profiles within the clinical cohort and the impact of this on clinical outcomes. The over-riding aim of each of the studies was to improve the clinical care of patients with HIV-1 infection in the UK.
Results: In the treatment-naïve patient cohort (n=380), a resistance prevalence rate of 16.5% was determined. In the treatment-experienced cohort (n=1,786), the resistance prevalence rate was 68.1%. Of those treatment-experienced, 91.3% would be susceptible to the new ARV Etravirine (ETV) and 89.7% to Darunavir (DRV). In the subtype patient cohort (n=1,642), an increase in the prevalence of pure and recombinant non-B subtypes over time was demonstrated and characterised, as well as the identification of polymorphisms specific to non-B subtypes compared to subtype B.
Conclusions: The resistance prevalence rate of >10.0% in the treatment-naïve patient cohort supported the need to conduct genotypic resistance tests for all treatment-naïve patients with HIV-1 infection before commencement of HAART in order to ensure the patient was starting on the optimal first-line treatment regimen to control their virus. National and European guidelines were subsequently amended to reflect this requirement. The treatment-experienced patient cohort analyses confirmed the resistance mutations circulating within the treated HIV-1 community which are the source of transmitted resistance to the treatment-naïve patients. Further analyses of the treatment-experienced cohort suggested two new ARVs which were due to be licenced for use with HIV-1 patients would be “theoretically susceptible”, providing further treatment options for these patients with resistance mutations. The subtype patient cohort work determined that subtype characterisation should be introduced as part of clinical care due to the impact of non-B subtypes on the success of genotypic resistance testing, and the different mutational pathways which might occur, leading to resistance in different subtypes.
All these studies provided data and evidence of current issues which impacted on the clinical care of patients living with HIV-1 in the UK and influenced changes in guidelines on how best to manage and improve patient care.
|Item Type:||Thesis (Doctoral)|
|Subjects:||Medicine and health > Clinical medicine
Medicine and health > Pharmacology
|Depositing User:||Marzena Dybkowska|
|Date Deposited:||02 Sep 2016 11:36|
|Last Modified:||02 Sep 2016 11:36|
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