The interplay of complex host and viral genetic differences is likely to play a huge role in determining pathologic outcomes in PWH. For example, differences in HIV strains/variants (Rao et al. 2013) and human/host genetic variability (Proudnikov et al. 2012), pharmacokinetics (Kuhlman et al. 1996; Eap et al. 2002; Elkader and Sproule 2005; Kharasch 2017; Kringen et al. 2017), and sex (Zubieta et al. 2002; Taylor and Davies 2010; Venuto et al. 2014; Marinho et al. 2019) all contribute to variability in responsiveness. The following subsections will focus on key factors affecting opioid and HIV comorbidity.