For people with HIV/hepatitis B virus (HBV) co-infection who develop comorbidities that require polypharmacy, treatment may be complicated due to drug interactions and overlapping toxicities of medications received. As the population with HIV ages, there are more patients developing malignancies and undergoing transplantation, and management can be complicated. This review describes the best strategies for the treatment of a hypothetical patient with HIV/HBV co-infection who develops diffuse large B-cell lymphoma and ultimately undergoes autologous haematopoietic stem cell transplantation. In this theoretical case, the patient is treated with bictegravir/emtricitabine/tenofovir alafenamide. Situations arise where people with HIV have underlying antiretroviral drug resistance and HBV drug resistance that require optimization of their antiviral therapy. As these types of cases are seen commonly at our institution, we discuss special situations that develop during treatment, including immune reconstitution inflammatory syndrome, that require close monitoring and occasional treatment modifications during their course of therapy.