DDIs become more relevant as PWH are aging, due to a higher prevalence of chronic conditions leading often to polypharmacy [7]. Moreover, the escalating popularity and accessibility of OTC medications and recreational drugs among PWH further compound this issue [8, 9]. Despite the existence of specialized HIV DDI websites (such as https://www.hiv-druginteractions.org, http://www.interaccionesvih.com, or https://www.hivmedicationguide.com) designed to assist healthcare providers in managing of DDIs, their content predominantly revolves around theoretical risks associated with DDIs. Many of DDIs, however, have never been evaluated in formal PK studies or assessed in clinical practice, leaving the clinical significance and outcomes of these interactions largely unknown. This gap in understanding is especially prominent in DDIs involving OTC medications and substances like recreational drugs, whose use is frequently undisclosed to healthcare providers.

In our study, boosted ARVs emerged as the most prevalent contributors to DDIs, accounting for 74 cases (53%) reported. This predominance can be attributed to the potent inhibition of cytochrome P450 (CYP) metabolism by ritonavir and cobicistat, which are integral components of boosting strategies [10]. The shift from boosted PI to unboosted InSTI reflects current treatment guidelines, wherein unboosted InSTI serve as first-line therapies. Unlike boosted PI, unboosted InSTI do not exert inhibition or induction effects on drug-metabolizing enzymes or transporters, rendering them favorable in terms of their DDI profile, with added advantage of achieving rapid virological suppression [11,12,13]. However, despite this shift, boosted PIs maintain clinical significance due to their utility in specific scenarios. They remain the preferred combination for individuals experiencing failure in pre-exposure prophylaxis (PrEP) with long-acting cabotegravir (LA CAB) as well as for those individuals with virological failure and the subsequent selection of drug resistance mutations during therapy with LA CAB plus LA rilpivirine [14, 15]. Consequently, DDIs associated with boosted PI retain relevance in clinical practice and might potentially gain increased importance in the future.

Of significance is the involvement of OTC medications in 20% of the reported cases, notably resulting in “loss of ART efficacy” in 63% of these instances. These cases predominantly featured the combination of unboosted InSTI with mineral supplements containing divalent cations, known to interfere with intestinal absorption of InSTI by chelation in the gastrointestinal tract [16, 17]. In most of these cases, the viral load was successfully resuppressed to undetectable values, either by discontinuing the supplements or by separating their intake from ARVs (Table 2). Consequently, in managing cases of virological failure, it becomes paramount for HIV healthcare providers to meticulously review medications, including non-prescription drugs, especially mineral supplements. Equally crucial is the necessity to educate patients about potential interactions, as many individuals may not perceive minerals, herbal supplements, recreational drugs, or other OTC products as “traditional medications” and they may not be aware of possible DDIs [18].

This study may be affected by some limitations. Firstly, case reporting relied solely on self-motivation of HIV healthcare providers, potentially introducing bias in both the number and content of the reported cases. Furthermore, the majority of reports were PK-based, and drug concentrations were available in only a few of them. However, the reporting of real-world DDI data to www.clinicalcasesDDIs.com is highly encouraged as it serves as a valuable resource for assessing the clinical relevance of DDIs. This becomes particularly crucial given the occasionally theoretical and conflicting information present in available electronic databases [6, 19]. Documenting real-world cases helps bridge knowledge gaps, ultimately enhancing the quality of care for PWH. Notably, the integration of real-world cases for clinical decisions on DDIs has been recently incorporated into the EACS HIV treatment guidelines [20].