Opening the Door on Entry Inhibitors in HIV

Redefining the Use of Entry Inhibitors in Heavily Treatment Experienced and Treatment-Limited Individuals Living With HIV

Chloe Orkin; Pedro Cahn; Antonella Castagna; Brinda Emu; P Richard Harrigan; Daniel R. Kuritzkes; Mark Nelson; Jonathan Schapiro


HIV Medicine. 2022;23(9):936-946. 

In This Article

Abstract and Introduction


Introduction: Entry inhibitors are a relatively new class of antiretroviral therapy and are typically indicated in heavily treatment experienced individuals living with HIV. Despite this, there is no formal definition of 'heavily treatment experienced'. Interpretation of this term generally includes acknowledgement of multidrug resistance and reflects the fact that patients in need of further treatment options may have experienced multiple lines of therapy. However, it fails to recognize treatment limiting factors including contraindications, age-associated comorbidities, and difficulty adhering to regimens.

Methods: This manuscript follows a roundtable discussion and aims to identify the unmet needs of those living with HIV who are in need of further treatment options, to broaden the definition of heavily treatment experienced and to clarify the use of newer agents, with an emphasis on the potential role of entry inhibitors, in this population.

Results/Conclusions: Within the entry inhibitor class, mechanisms of action differ between agents; resistance to one subclass does not confer resistance to others. Combinations of entry inhibitors should be considered in the same regimen, and if lack of response is seen to one entry inhibitor another can be tried. When selecting an entry inhibitor, physicians should account for patient preferences and needs as well as agent-specific clinical characteristics. Absence of documented multidrug resistance should not exclude an individual from treatment with an entry inhibitor; entry inhibitors are a valuable treatment option for all individuals who are treatment limited or treatment exhausted. We should advocate for additional clinical trials that help define the role of entry inhibitors in people with exhausted/limited ART options other than drug resistance.


With over 37 million individuals living with HIV worldwide at the end of 2018, HIV infection remains an important clinical challenge. Increasing access to effective prevention and treatment, and ongoing improvements in antiretroviral therapy (ART) have led to reductions in both morbidity and mortality and mean that HIV has largely become a manageable chronic condition.[1] Since the discovery of HIV in 1983, over 30 drugs and their combinations have been approved for clinical use.[2,3] Using these combinations, it is possible to suppress the virus for the majority of individuals living with HIV; however, a small proportion of individuals who are 'heavily treatment experienced' (HTE) reach a point where antiretroviral regimens are no longer suppressive. Despite common use of the term 'HTE', it has no universally accepted definition, making it difficult to determine the number of individuals living with HIV who are HTE. A retrospective cohort study of commercial and Medicare Advantage health plan enrollees in the USA between 2013 and 2019 found that 16.1% of 14 258 people living with HIV were THE.[4] An ongoing cohort study of 22 000 Europeans living with HIV estimates that approximately 10% are HTE, with this figure rising from just 5.8% in 2010 to 8.9% in 2016.[5] Conversely, a study of ART-experienced individuals with HIV living in the USA found that the number with limited remaining treatment options declined from 5.2%–7.8% in 2000–2006 to <1% from 2012 through 2017.[6] Clearer definition of HTE is needed to help physicians identify those in need.

In order to treat HTE individuals living with HIV, novel agents are needed. Three new agents have recently been approved in HTE individuals living with HIV: fostemsavir, a gp120-directed attachment inhibitor (2020); ibalizumab, a CD4-directed post-attachment inhibitor (2018); and albuvirtide, a fusion inhibitor (2018).[7–9] Ibalizumab and fostemavir are first-in-class agents, and all three fall in to the broader group of entry inhibitors, which prevent viral entry into host CD4+ cells. These drugs are associated with different side effect profiles and contraindications.[7,8,10,11]

In the past, individuals with documented multidrug resistance were recruited to trials of entry inhibitors,[12–15] aligning with traditional – yet informal – definitions of HTE. However, HTE is not the sole reason for the need for new agents. For example, being older with multiple age-associated comorbidities and a need to consider drug–drug interactions or complex polypharmacy regimens could necessitate regimen simplification and therefore a desire for new ARTs. Although many of the factors associated with treatment exhaustion/limitation may be present in those who are HTE, they can also exist independently of multidrug resistance and duration of treatment experience, necessitating the coining of a new term to identify individuals who are not HTE but simply in need of new treatment options. This paper identifies and defines individuals living with HIV in need of alternative/novel treatment options; we also discuss the benefits and challenges of new antiretroviral therapies.