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Department of Experimental and Clinical Pharmacology
College of Pharmacy
University of Minnesota
Melanie Nicol, PharmD, PhD, has no relevant financial relationships to disclose.
Long-awaited, long-acting injectable medications are now available for both the treatment and prevention of HIV, bringing new options that, for the first time in the history of HIV care, do not require taking 1 or more pills every day. In this commentary, I review key differences among available HIV pre-exposure prophylaxis (PrEP) medications and the potential role of individual pharmacokinetic variability in the efficacy of long-acting options for PrEP and antiretroviral therapy (ART).
Expanded PrEP Options
Ten years after the first PrEP medication approval, we are now in an era with 4 different PrEP options:
With this array of options each having unique characteristics and, in some cases, demonstrated efficacy limited to certain types of sex or gender, shared decision-making can be applied based on individual preference and clinical scenario.
Choosing Among Oral PrEP Options
Daily oral FTC/TAF and FTC/TDF appear to have similar prevention efficacy among men who have sex with men (MSM) and transgender women (TGW). Data on FTC/TAF efficacy among cisgender women are not yet available. When comparing the 2 daily oral options, FTC/TDF may be more useful in some patients based on a potentially lower cost, availability of data supporting the efficacy of event-driven rather than daily dosing for cisgender men, lower risk of dyslipidemia or weight gain, and availability of data supporting protection against vaginal HIV transmission. By contrast, FTC/TAF has a wider safety margin regarding kidney and bone adverse effects vs FTC/TDF and can be safely used in individuals with estimated glomerular filtration rates as low as 30 mL/min.
Long-Acting Injectable PrEP
Long-acting injectable CAB administered every 2 months has several important features distinguishing this option from oral PrEP, in addition to the obvious difference in dosing modality. Of note, long-acting CAB does not require renal or lipid monitoring and offers a “tenofovir-free” option that was demonstrated to have superior HIV prevention efficacy vs daily oral FTC/TDF in both MSM/TGW (HPTN 083) and cisgender women (HPTN 084). Long-acting CAB can be an option for individuals who prefer not to adhere to a daily tablet but are amenable to clinic visits every 2 months.
What We Have Learned From Long-Acting PrEP Trials
Recent data from the HPTN 083 trial have increased awareness of the potential for delayed diagnoses in individuals acquiring HIV in the setting of ongoing PrEP use. The potential for these individuals to develop drug resistance while continuing to receive PrEP before the identification of incident HIV infection has also been recognized. The CDC’s revised recommendation to add HIV-1 RNA testing to antigen/antibody testing when monitoring for incident HIV while receiving any PrEP option certainly makes sense in this context because of the increased detection sensitivity. However, this recommendation has been incredibly challenging to implement in many settings.
Although rare, breakthrough infections on long-acting CAB PrEP have occurred, and unlike with oral PrEP where most breakthrough infections have been historically attributed to imperfect adherence or to transmission of drug-resistant variants, breakthrough with long-acting CAB has been observed even in the setting of on-time injections. To date, breakthrough with on-time injections has only been reported in MSM/TGW in HPTN 083, raising the question of whether the differences in drug exposure between colorectal and cervicovaginal tissue may be implicated. The long-term effects of HIV diagnostic delays on drug resistance rates among people who acquire HIV infection while receiving long-acting CAB as PrEP, particularly integrase strand transfer inhibitor resistance, is unknown.
Long-Acting ART as Treatment: Does Pharmacokinetic Variability Play a Role in Rare Cases of Failure?
With the new long-acting injectable HIV treatment option, CAB plus rilpivirine (RPV), it is also possible that pharmacokinetic variability plays a role in risk for virologic failure. Although injectable CAB plus RPV has also been demonstrated to be remarkably effective at maintaining viral suppression when used as a switch regimen for people with viral suppression on oral ART, a small number of virologic failures have been reported despite on-time injections.
Identifying factors to predict who is at higher risk of virologic failure is of significant ongoing clinical interest. In addition to baseline RPV resistance mutations and HIV-1 subtype (A6/A1), lower drug troughs and factors associated with lower drug troughs (ie, higher BMI) seem to be important risk factors for virologic failure with long-acting CAB plus RPV, but it is not yet clear whether therapeutic drug monitoring would be of benefit to identify variable pharmacokinetics among individuals.
Long-acting injectable strategies are here for both the treatment and prevention of HIV, adding a new paradigm to the armamentarium for management of an individual’s HIV therapy or for their sexual health preventive care. In theory, unaccounted for variability in pharmacokinetics may explain rare cases of PrEP and treatment failure with the new long-acting approaches, but how this variability may influence patient care is an area of ongoing research. Optimal management and implementation of these new modalities will continue to develop during the coming months and years, and the community eagerly awaits the arrival of even more long-acting options in the future.
Have you incorporated long-acting HIV treatment or prevention strategies into your clinical practice? Join the discussion and share your experiences by posting a comment.