Long-acting injectables (LAI) represents one of the most significant advances in antiretroviral therapy in recent years, offering durable suppression for PLWH who find daily oral medications challenging. Confirmed virological failure (CVF) is a low-incidence (1.4% over 152 weeks) but high-consequence event, with almost all developing drug-resistant mutations. This is in contrast to daily oral INSTI-based regimens.
Risk factors for CVF with LAI therapy are well-characterised and include having 2 or more of the following risk factors: i) prior rilpivirine resistance associated mutations, ii) HIV subtype A1/A6 and iii) BMI ≥30kg/m2. In real-world deployment, CVF can be minimised through careful selection of patients for LAI. However this could exclude significant numbers of people for whom LAI would have the greatest benefit, since stigma, the need for treatment concealment and the psychological challenges of daily oral medications affects so many people.
In combined analyses, 82% (18/22) of participants with CVF had low predicted plasma trough concentrations of cabotegravir or rilpivine (lowest quartile). LAIs are associated with considerable inter- and intra-patient variability. In the latter case, injection-to-injection variability is likely to be a dominant contributory factor. This pharmacokinetic variability has led to some calls for therapeutic drug monitoring but its availability, feasibility and the scope of actions that should follow are some of the many barriers to uptake.
Is LAI therapy incremental or transformative ? In public health terms, pragmatic limits to delivery (based on current service models) and careful case-selection (to limit CVF) lean to the former, making this a valuable addition to the existing armamentarium of drugs. To be transformative, LAIs need to reach those who would not otherwise be treated, and to suppress those who would otherwise fail. These are generally populations explicitly excluded from pivotal trials. Recent clinical studies in these challenging populations provide important evidence that LAIs could be transformational, and this work will be reviewed.