Detection and significance of drug- resistant HIV-1 minor populations
Year: 2008
Type: dissertation
Study design: Observational Study
Abstract: The human immunodeficiency virus (HIV) is the cause of the HIV/AIDS \npandemic affecting millions of people around the world. Treatment with \nantiretroviral drugs, if used properly, leads to a dramatic decrease in \nvirus production in the patient and prevents the onset of AIDS. However, \ntreatment is not always successful, mainly due to the extraordinary \nability of the virus to change and become resistant to the antiretroviral \ndrugs. \n \n \n \nThe general aim of this thesis was to study the development of HIV-1 drug \nresistance, specifically the detection and significance of small \npopulations of drug-resistant virus in infected individuals that can go \nundetected by the standard resistance tests used in the clinics today. In \nstudy I, we developed and evaluated an assay called selective real-time \nPCR (SPCR), which can detect and display the proportions of different \npopulations of drug-resistant virus carrying the clinically relevant \nM184I/V mutations in the HIV-1 reverse transcriptase enzyme. These \nmutations confer high-level resistance to one of the most commonly used \ndrugs today, lamivudine (3TC). The SPCR assay was then applied to several \ndifferent clinical cohorts in the subsequent papers. \n \n \n \nWe found SPCR to be a well-functioning, sensitive and reliable method to \nstudy the kinetics of antiretroviral resistance development in HIV-1, \nwhich was able to detect resistance mutations not seen by conventional \ngenotyping assays. \n \n \n \nIn study II, we evaluated the presence of M184I/V-containing minor viral \npopulations and their potential role in treatment failure in didanosine \n(ddI)-treated patients experienced with multiple nucleoside reverse \ntranscriptase inhibitors. We found that the survival advantage of virus \nstrains having the M184I/V mutations were limited during ddI treatment, \nsuggesting that the presence of these mutations should not preclude the \nuse of ddI in nucleoside-experienced patients. \n \n \n \nIn study III, we investigated to which extent unique drug resistance \npatterns appear in cerebrospinal fluid as compared to blood in patients \nwho had failed 3TC-containing therapy. We found differences in drug \nresistance patterns in both minor and major populations, which were \nlikely to be related to differences in the selective pressure of \nantiretroviral drugs within the two compartments rather than unique \nevolutionary pathways. Minor populations were not seen to play a major \nrole in resistance development in cerebrospinal fluid in the patients we \ntested. \n \n \n \nIn study IV, we studied to which extent selection of M184I/V mutations \noccurs in treatment-naïve patients during the first months after \ninitiation of antiretroviral therapy containing two, three or four drugs. \nWe found the selection of drug-resistant variants to be rare in the \nthree- and four-drug cohorts, but common in the two-drug cohort, \nsuggesting that current treatment regimens initiated in treatment-naïve \npatients should be sufficient to stop resistance development during the \nfirst phase of viral decay, as long as the patients are adherent. \n \n \n \nThe clinical significance of minority populations in the development of \nresistance to antiretroviral drugs is an important topic to be defined. \nSPCR and similar assays will provide valuable tools to further expand the \ncurrent knowledge in this field.
Source: Figshare
Author: Tobias Bergroth
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1787424918