Primary HIV drug resistant mutations are mutations that occur in an HIV-infected individual prior to the initiation of antiretroviral therapy (ART). These mutations may arise by de novo mutagenesis or result from transmission. Drug resistant mutations (DRMs) may reduce the effectiveness of ART leading to inadequate virological outcomes. Currently, Sanger sequencing is the standard method for detection of DRMs to inform treatment decisions, but does not detect minor variant mutations. Drug resistant minority variants (DRMVs) can be detected by next generation sequencing (NGS). However, several challenges including cost of infrastructure and the need for complex data analysis bioinformatics tools remain major setbacks for NGS use. More importantly, the clinical impact of DRMVs on ART is not well understood, underscoring the importance for understanding whether the levels of primary DRMVs for different mutations impact on the effectiveness of ART and the rationale for inclusion in routine diagnostics. Understanding the impact of primary DRMVs will help inform how NGS may be utilized in the future for pre-emptive clinical ART decision making.