Early bictegravir failure and emergence of R263K-mediated class-wide HIV integrase inhibitors resistance linked to over-the-counter supplement use

A 33-year-old male of 60 kg, with no previous medical history, except for a recent episode of ophthalmic herpes zoster, presented in July 2021 with dyspnoea and weight loss, leading to the diagnosis of Pneumocystis pneumonia and newly diagnosed HIV infection at an AIDS stage (CDC C3). The viral load was at 6.80 log copies/mL and CD4+ T cell count revealed profound depletion (36 CD4/mm3). Antiretroviral therapy (ART) was initiated on day 14 using a single tablet regimen (STR) combining bictegravir/emtricitabine/tenofovir alafenamid (BIC/FTC/TAF). Resistance mutation analysis (ANRS protocol, CEQ8000 Beckman) only revealed V106V/I, a polymorphic accessory mutation associated with non-nucleoside reverse transcriptase inhibitors. However, the viral load remained high, at 1 month (M1: 6.59 log RNA copies/mL) and 3 months (M3: 6.02 log RNA copies/mL) after ART initiation (Table 1). Despite reported perfect adherence, a new complete resistance genotyping revealed the emergence of two resistance mutations: R263K, conferring complete resistance to integrase strand transfer inhibitors (INSTIs), and M184V, selected by emtricitabine (FTC), which is associated with high-level resistance (>200-fold reduction in susceptibility) and decreased viral fitness.1 Therapeutic drug monitoring of BIC, FTC and TAF was performed on 8 and 11 October 2021. Plasma concentrations of FTC and TAF were within the expected therapeutic range while BIC plasma concentrations were markedly reduced suggesting a likely subtherapeutic exposure (Table 2). This pharmacologic pattern was unexpected, due to the STR formulation. On further investigation, the patient reported taking an over-the-counter multivitamin supplement (AZINC vitalité®) containing divalent cations (15 mg Zn2+, 3.5 mg Mn2+, 8 mg Fe2+, 120 mg Ca2+), which probably caused a drug–drug interaction (DDI) with BIC. In October 2021, the viral load reached 5.6 log RNA copies/mL and treatment was switched from BIC/FTC/TAF to doravirine/tenofovir disoproxil/lamivudine combined with ritonavir-boosted darunavir, in accordance with the genotypic resistance profile of the viral strain.