Keywords: HIV; seroconverters; primary resistance; key mutations; progression; CD4; subtype; HIV RNA; HAART; survival
The overall aim of this project is to study the virological characteristics of new HIV-1 infections from around Europe. The project will focus on the HIV-1 subtypes, which are a reflection of the worldwide geographical origin of infections, and the presence of drug resistant strains, which, if present in primary infection, represent transmission of drug resistant virus. A number of cohorts of persons with known dates of HIV seroconversion (seroconverters) enrolled within the CASCADE will be utilised.
CASCADE has described the lack of change in the AIDS incubation period and survival in Europe prior to the introduction of potent anti-retroviral therapy combinations in the mid-1990s. The clinical course of HIV disease has improved dramatically since the introduction of highly active anti-retroviral therapy (HAART) and CASCADE has been able to quantify such change by providing estimates of the current survival expectations. However, the number of new infections within Europe continues to rise. The unfolding of the epidemic during this period has been characterised by two key virological parameters, which have potential bearing on the incubation period and survival in seroconverter cohorts. Firstly, the emergence of drug resistance in treated individuals has led to the transmission of resistant virus strains. Secondly, the ongoing migratory patterns into,and within Europe has been associated with the introduction of a wider variety of HIV-1 subtypes then had previously existed. One of the main characteristics of HIV is its extensive genetic diversity. The major group circulating globally is M, which can be divided into a number of subtypes, based on genomic relatedness. These subtypes (A-K), as well as 11 recombinant forms, are geographically distributed, and therefore represent a marker of migration. It is expected that these diverse viruses will be further spread within Europe by the ongoing epidemic.
The aims of this project are:
1) to estimate the association between the pattern of genotypic resistance
and virological, immunological and clinical outcome
2) to estimate to what extent, if any, infection with drug resistant HIV affects response to first-line therapy
3) to examine differences in HIV RNA levels in persons infected with different HIV subtypes who have similar CD4 levels
4) to examine changes in the prevalence of HIV drug resistance in primary infection over time
5) to examine factors associated with differences in primary resistance prevalence estimates, such as age; exposure category, sex and country of infection
6) to examine the evolution of key mutations over time in the absence of antiretroviral therapy.
1) Report on the association between infection with drug resistant HIV and
response to first-line therapy.
2) Report on the association between the initial pattern of genotypic resistance and virological,
immunological and clinical outcome.
3) Report on differences in HIV RNA in persons infected with different HIV subtypes with similar CD4 levels.
4) Report on changes in the prevalence of HIV drug resistance in primary infection.
5) Report on factors associated with transmitted resistance mutations.
6) Report on evolution of key mutations detected at the time of seroconversion in treated and untreated persons.
7) Compile a high quality pooled dataset of data on transmitted drug resistant HIV, HIV subtype and epidemiolgic and clinical data on persons with known dates of HIV seroconversion.
Data arising from this study will be crucial to assessing whether HIV-1 drug resistance testing should be undertaken in primary infection alone, or in all new HIV-1 diagnoses. Such information will allow for more individualised HIV-1 therapy at the initiation of treatment.
Results will help reinforce the public health messages regarding the importance of safe sex in preventing the spread of drug resistant HIV-1 and in providing an epidemiological basis for decisions on the allocation of HIV prevention resources to new migrant communities within Europe.