From bedside to bench and back : future options for antiretroviral drugs in non-B HIV-1 subtypes

Sammanfattning: HIV-1 drug resistance remains a burden in low- and middle-income countries (LMIC). Regardless of the advances in antiretroviral (ARV) therapy, there is an increase in the trend of acquired and pre-treatment drug resistance mutations (DRM) in LMIC affected by diverse HIV-1 subtypes. In the work presented in this thesis, I investigated the prevalence of HIV-1 acquired drug resistance (ADR) in South Africa from the period 2006-2014 (Paper I). Additionally, the in vitro protease- inhibitor (PI) drug sensitivity assay (DSA) response of HIV-1 subtype C (HIV-1C) derived recombinant viruses was compared to non-C viruses to understand their susceptibility profile to PI drugs. Results for the prevalence of ADR, specifically for patient sequences treated with a PI-based regimen (n=1043), was found to be <9%. No significant subtype-specific differences were seen for viruses tested in the DSA for Darunavir (DRV), Lopinavir (LPV) and Atazanavir (ATV) susceptibility. In Paper II, it was hypothesized that the gag gene could play a role in the response of PIs in the absence of known PI primary mutations. Hence to understand the role of Gag in impacting PI susceptibility and viral fitness, the gag-p6 region was specifically investigated. The study showed an increase in viral fitness for HIV-1C viruses carrying the PYxE insertion in gag-p6 when compared to the wild-type (WT) HIV-1C viruses. Furthermore, some PYxE-carrying viruses had low sensitivity to LPV and Tenofovir alafenamide (TAF) when tested in DSAs. Clinical data analysis, showed a higher pre-therapy viral load and a decrease in CD4+ T-cell counts for patients harboring PYxE-carrying viruses when compared to WT. It was also essential to understand the inhibitory potential of most clinical (new and old) drugs used mainly to treat non-B HIV-1 subtypes. Hence, in Paper III, the newer antiretroviral drug 4’-Ethynyl-2’-Fluoro-2’ deoxyadenosine (EFdA), was compared to TAF, first and second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs). It was demonstrated that EFdA has a high inhibitory potential independent of HIV-1 subtype and high antiviral activity against resistant viruses. However, HIV-1C viruses had a significantly reduced susceptibility to NNRTIs, specifically Rilpivirine and Etravirine. Finally in Paper IV, the drug susceptibility of Integrase strand transfer inhibitors (INSTIs) against diverse HIV-1 subtypes was investigated. Results indicated that INSTIs such as Dolutegravir (DRV), Bictegravir (BIC) and Cabotegravir (CAB) inhibited non-B subtypes significantly as compared to HIV-1B subtypes. Finally, inferences suggest that subtype-specific differences play an essential role in influencing the ARV susceptibility which could further impact the treatment efficacy in sub-optimal adherence. To reduce the trend of increasing DRMs in non-B HIV-1 subtypes which are mainly dominating in LMICs, adherence support and viral load monitoring should be prioritized. A rapid adaptation of INSTIs and newer drugs that have long-acting potential is encouraged. However, pre-clinical studies and clinical trials that are mainly restricted to HIV-1B enrolled patients, should be inclusive of non-HIV-1B infected patients before the massive roll-out of INSTIs and newer drugs continues in non-HIV-1B dominated settings.