Antiretroviral drug resistance and treatment outcomes of human immunodeficiency virus type-1, implications for low and middle income countries

Sammanfattning: My thesis contains comprehensive studies of antiretroviral treatment (ART) naïve and experienced patients from the beginning of the Swedish HIV-1 epidemic. Paper I was the first study to describe the ART usage and occurrence acquired drug resistance mutations (DRM) at a population level in Sweden over time and we used data derived between 1997-2011. We showed that there was a general decrease of DRM to PIs and NRTIs, while an increase of DRM towards NNRTIs was found in patients from low-and middle-income countries (LMICs) with ART initiation after 2007. We therefore suggest that treatment regiments without NNRTI and their effectiveness tested for non-B-subtypes should be considered as first-line choice for patients from LMICs. In Papers II, III and IV I focused on the impact of different subtypes. At the start of the epidemic HIV-1B dominated in high-income countries and due to migration and traveling changes occurred in the global subtype distribution. Temporal trends of various subtypes in Sweden were unknown until analyzes presented in Paper II were preformed. In that study we showed an increasing trend of HIV-1C and recombinant forms and a decline of HIV-1B in newly diagnosed patients. Our results suggest that this is partly due to spread of non-B subtypes among heterosexuals and MSM within the country. Papers III, IV and V analyzed treatment outcomes with special focus on subtype HIV-1C (III and IV) and consequences of reasons for treatment switch (V). In Paper III we demonstrated a significantly higher risk of viral failure for patients infected with HIV-1C using PI-based ART compared to HIV-1B. In Paper IV we analyzed drug resistance to second-generation NNRTI rilpivirine (RPV) among patients failing NNRTIs in Europe and in ART-naive HIV-1C infected patients from Ethiopia and India. RPV-inhibition and binding affinity assays on HIV-1C reverse transcriptase was also performed. Our findings indicate that the use of RPV has limitations in HIV-1C dominated countries where laboratory monitoring is not standard of care. In Paper V we studied the effects of different reasons for therapy switch and found that higher viral load (VL) at switch from first-line ART had a negative effect on time to second line ART failure, nevertheless no effect of VL-level and DRM on the CD4+ T-cell gain, AIDS or death was found. In conclusion, the treatment outcome of HIV-1 infected patients in Sweden has shown remarkable improvements and is now very good. Prevalence of DRM is low and once viral failure with or without DRM occurs patients are managed effectively. Nonetheless the virus and the epidemic are highly heterogeneous and constantly changing, requiring close surveillance. Also our studies reveal new future challenges for the optimization of ART in patients infected in LMICs in terms of effectiveness on non-B subtypes.