Predicted antiviral activity of tenofovir versus abacavir in combination with a cytosine analogue and the integrase inhibitor dolutegravir in HIV-1 infected patients initiating or failing first-line antiretroviral therapy in Southern Africa

Synopsis Objectives The WHO recently recommended the use of a new first-line antiretroviral therapy (ART) containing dolutegravir. We investigated efficacy of nucleoside reverse transcriptase inhibitor (NRTI) backbones (tenofovir or abacavir with cytosine analogue) in low- and middle-income countries where there is significant prior exposure to antiretrovirals and drug resistance to NRTI. Methods Within the treatment as prevention study, South Africa, we selected participants with available next generation sequencing (NGS) data for HIV-1 pol gene at trial entry; they were either ART initiators (n=1193) or already established on ART (n=94). NGS of HIV-1 pol gene was carried out using MiSeq technology: RT drug resistance mutations (DRM) were detected at 5% (DRM5%) and 20% (DRM20%) for all 1287 participants. Genotypic susceptibility was assessed using the Stanford HIVDB resistance interpretation algorithm. Results NRTI DRM20% and DRM5% were detected among 5/1193 (0.4%) and 9/1193 (0.8%) of ART initiators respectively. There was tenofovir exposure in 71/94 (75.5%) of those with prior ART, with full susceptibility to abacavir in 57/94 (60.6%) and 56/94 (59.6%) for DRM20% and DRM5% respectively, while 67/94 (71.3%) and 64/94 (68.1%) were fully susceptible to tenofovir respectively. The differences between tenofovir and abacavir were not statistically significant at 20 or 5% variant level (p=0.16 and 0.29 respectively). NGS detection of variants at 5% level increased detection of K65R in both naive and treated groups. One of 643 integrase sequences carried a DRM20% (Q148R). Conclusion Dolutegravir with cytosine analogue plus tenofovir or abacavir appear to have similar efficacy in South Africans naive to ART. NGS should be considered in HIV drug resistance surveillance