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Published in final edited form as: Expert Opin Pharmacother. 2024 Jan 5;24(18):1949–1956. doi: 10.1080/14656566.2023.2294918

Expanding therapeutic options: lenacapavir + bictegravir as a potential treatment for HIV

Jessica Doan 1, Shannon Brunzo-Hager 1, Brittany Satterly 1, Theodore James Cory 1
PMCID: PMC10786069  NIHMSID: NIHMS1952560  PMID: 38164956

Abstract

Introduction:

Treatment for people with HIV/AIDS has radically evolved since the introduction of the first antiretrovirals. One newly approved antiretroviral is lenacapavir, which targets the viral capsid. Lenacapavir is currently approved as a therapeutic addition for subjects who are treatment-experienced, and who have developed resistance to multiple antiretrovirals. It is available both as a daily oral tablet and a once every six month subcutaneous injection. It is currently undergoing clinical trials in combination with the integrase inhibitor bictegravir as a dual therapy option, both for treatment experienced and treatment naïve individuals.

Areas Covered:

We reviewed published articles, conference proceedings, and clinical trial databases to assess the current status of the research into lenacapavir and bictegravir. While the clinical trials are ongoing, with little published data to date, this combination shows promise for the treatment of both treatment experienced and naïve patients. We review the studies relevant to the pharmacokinetic/pharmacodynamic properties of the drugs.

Expert Opinion:

The new combination with bictegravir will be beneficial for treatment experienced patients, as it represents a dual therapy modality with high barriers of resistance. As a therapy for treatment naïve patients, its use is likely more niche, as other combinations are available.

Keywords: antiretroviral, bictegravir, Capsid inhibitor, HIV-1, lenacapavir

1.0. Introduction

Human immunodeficiency virus type 1 (HIV-1) has been prevalent since 1981 when Acquired Immune deficiency Syndrome (AIDS) was first noted as a new disease; HIV-1 has since evolved into a global pandemic that researchers are working to end [1]. As of the end of 2022, there are approximately 39 million people living with HIV (PLWH) in the world [2]. The Joint United Nations Program on HIV/AIDS (UNAIDS) has developed an ambitious plan to reach 95% of PLWH knowing their HIV status, 95% of PLWH who know their HIV status starting treatment, and 95% of PLWH on treatment being virally suppressed by 2025, with the goal of ending AIDS as a public health threat by 2030 [3].

The first treatments for HIV-1 were developed in the late 1980s and consisted of monotherapy with the nucleoside reverse transcriptase inhibitor (NRTI) azidothymidine [4,5]. After the development of azidothymidine, new classes of anti-HIV medications, such as protease inhibitors (PIs) and integrase strand transfer inhibitors (INSTIs) have been developed to further provide effective control of HIV in patients [4]. The newest FDA-approved antiretroviral medication, lenacapavir (LEN), is the first approved drug of the newest class of medications known as capsid inhibitors [6]. LEN is FDA approved for use in PLWH failing their current antiretroviral treatment due to multidrug resistant HIV-1 infection [7]. Injectable LEN is also being explored for use in people without HIV needing pre-exposure prophylaxis (PrEP) to prevent HIV acquisition, since it can be administered once every six months after a loading cycle [7]. Clinical trials are currently exploring the safety and efficacy of LEN as combination therapy with bictegravir (BIC) compared established regimens [8]. Information summarizing these drugs can be found in the drug summary table (Table 1).

Table 1.

Drug Summary

Drug Name Bictegravir Lenacapavir
Phase Phase I/II/III, ongoing phase II/III
Indication HIV-1 infection
Pharmacology Description / Mechanism of Action Integrase strand transfer inhibitor (INSTI) HIV-1 capsid inhibitor
Route of Administration Oral Oral, Subcutaneous injection
Chemical Structure graphic file with name nihms-1952560-t0001.jpg graphic file with name nihms-1952560-t0002.jpg
Pivotal Trials NCT02275065, NCT05502341 CAPELLA, CALIBRATE, NCT05502341
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2.0. Overview of the Market

Since its introduction, antiretroviral therapy has radically transformed the care for PLWH. The increase in demand for antiretroviral therapy for HIV treatment is driven by enhanced diagnostic capabilities, progress in treatment methodologies, increased access to care, and the advent of innovative drugs with higher efficacy and resistance profiles [9]. This is further bolstered by heightened public awareness and healthcare initiatives. UNAIDS has set in motion the ambitious Fast-Track strategy with the objective of eradicating the AIDs epidemic by 2030 [10]. This strategy focuses on optimizing resource allocation and expedited responses. Generally, in the United States and Europe patients will be started on a regimen consisting of two NRTI agents, and a third agent, most commonly an integrase strand inhibitor. However, there are several other therapeutic options that can be utilized[11].

The global market for HIV treatment is divided amongst several combination single tablet antiretroviral regimens. There are over 30 available medications available for antiretroviral treatment worldwide. In 2022, the combination of tenofovir alafenamide, emtricitabine, and BIC has dominated the global HIV treatment market. This combination is preferred by clinicians and patients due to its high efficacy, minimal side effects, convenience, and effectiveness across diverse patient populations. It is projected that by 2030 the HIV market will grow due to advancements in research and development especially with injectables and gene therapies as well as the arrival of generics of medications which are currently only available as brand name products [12]. The ongoing support by the President’s Emergency Plan for AIDS Relief (PEPFAR) has also greatly increased disease outcomes globally [13]. From the initiation of PEPFAR in 2004, the number of persons living with HIV receiving ART increased 300 times in 54 countries due to expansion to medication access, testing, public awareness campaigns, and changes to national HIV guidelines [13].

3.0. Introduction to the Compounds

3.1. Chemistry

3.1.1. Bictegravir

Bictegravir, previously known as GS-9883, is an integrase strand transfer inhibitor (INSTI). It is a monocarboxylic acid amide with a trifluorobenzyl tail with favorable π-stacking interactions to the base of the viral DNA that increases the potency and resistance profile [14]. The bicyclic ring contributes to tighter binding and longer half-life [14]. It has a molecular formula of C21H17F3N3NaO5 and a molecular weight of 471.4 g/mol. BIC is an off-white to yellow solid with a solubility of 0.1 mg/mL in water at 20°C [15].

3.1.2. Lenacapavir

Lenacapavir, previously known as GS-6207, is a HIV-1 capsid inhibitor. The crystal structure of LEN binds to monomeric capsid proteins (CA) and establishes hydrophobic interactions, two cation-π interactions, and seven hydrogen bonds to the CA hexamers, it therefore competitively interrupts capsid interactions with the host’s proteins [16]. It has a molecular formula of C39H31CIF10N7NaO5S2 and a molecular weight of 990.3 g/mol. LEN is a light yellow-yellow solid and insoluble in water [17].

3.2. Pharmacokinetics (PK) and metabolism

3.2.1. Bictegravir

BIC possesses an oral bioavailability of over 70%; the AUC and Cmax of the drug can be increased 24% and 13%, respectively by concurrent administration of the medication with a high fat meal[15,18]. In a multiple dose regimen of BIC, the average Cmax is 6.15 μg/mL, the average AUC is 102 μg*h/mL, and the average trough concentration is 2.61 μg/mL [15]. The median time to reach the peak plasma concentration (Cmax) of BIC in people living with HIV (PLWH) is approximately 2 – 4 hours post dose administration. BIC demonstrates an exceptionally high rate of protein binding, with over 99% of the drug being bound to albumin[19]. The blood-to-plasma ratio of this drug is 0.64[15]. BIC primarily undergoes metabolism by CYP3A4 and UGT1A1. Approximately 60% of the drug is excreted in the feces as its oxidative metabolites, while 35% percent of the drug is renally excreted as its glucuronidated metabolite and less than 1% renally excreted as unchanged drug[18]. In PLWH, the elimination half-life (t1/2) of BIC is approximately 17 hours[20].

3.2.2. Lenacapavir

The oral bioavailability of LEN is between 6% – 10%; no pharmacokinetic parameters for this medication are affected by food[21]. The time to reach Cmax is approximately 4 hours after the oral dose is administered. However, the single-dose, oral pharmacokinetics are non-linear and less than dose-proportional[21]. Data regarding the concentration of oral LEN is based on a regimen where 600 mg of LEN is given by mouth on days 1 and 2, followed by 300 mg of LEN by mouth on day 8 and 927 mg of LEN subcutaneously on day 15; with this LEN regimen, the average Cmax is 69.6 ng/mL, the average AUC is 15,600 ng*h/mL, and the average trough concentration is 35.9 ng/mL [21]. Approximately 99.8% of LEN is protein bound. While it is not extensively metabolized, LEN is primarily metabolized by CYP3A4 and UGT1A1[21]. IV administered radiolabeled LEN in healthy individuals showed that 76% of the drug was excreted in the feces while less than 1% of the radioactivity was found in the urine. With the oral formulation of the medication, the median t1/2 is approximately 10 – 12 days[21].

4.0. Clinical Efficacy

4.1. Phase I Trials

4.1.1. Bictegravir

A Phase I trial of BIC alone was conducted with a quadruple-blinded, randomized, placebo-controlled study design; subjects in this study were administered BIC at a dose ranging from 5 mg to 100 mg once daily for 10 days [22]. The time-weighted average change in plasma HIV-1 RNA copies from baseline through day 11 (DAVG11) was measured and showed that as the dose of BIC was increased, there was a greater decrease in HIV-1 RNA copies, with the group receiving BIC 100 mg once daily experiencing a 1.61 log decrease in HIV-1 RNA copies [22]. Regarding safety, no severe adverse effects or mortality were reported with any dose of BIC. The most common side effects subjects experienced were headache, diarrhea, fatigue, and musculoskeletal pain; there was no correlation between the occurrence of side effects and the dose of BIC administered [22].

4.2. Phase II/III Trials

4.2.1. NCT02397694

NCT02397694 was a phase 2, double-blinded, randomized study, 98 participants were randomized (2:1) to receive oral once daily 75 mg BIC or 50 mg dolutegravir with combination of 200 mg emtricitabine and 25 mg tenofovir alafenamide for 48 weeks [23]. The primary outcome was the percentage of participants with HIV-1 RNA concentrations of less than 50 copies/mL at week 24, which was 96.9% in the BIC group and 93.9% in the dolutegravir group [23]. The most common adverse effects were GI upset [23]. Both treatment groups showed high efficacy and tolerable adverse effects at 24 weeks, but there was no statistical difference between the two treatments.

4.2.2. CALIBRATE

CALIBRATE is an ongoing phase 2, randomized, open-label, active-controlled trial (ClinicalTrials.gov Identifier NCT 04143594) enrolled 183 participants to four groups: 1) subcutaneous (SQ) LEN every 26 weeks with oral daily emtricitabine and tenofovir alafenamide for 28 weeks, followed by SQ LEN plus daily tenofovir alafenamide 2) SQ LEN every 26 weeks with oral daily emtricitabine and tenofovir alafenamide for 28 weeks, followed by SQ LEN plus daily BIC 3) oral daily LEN with emtricitabine and tenofovir alafenamide 4) oral daily BIC, emtricitabine, and tenofovir alafenamide as a standard of care [24]. Groups 1 and 2 were given two weeks of oral loading doses of 600 mg LEN on days 1 and 2, followed by 300 mg on day 8 [24]. Within 28 weeks of therapy, participants rapidly reached virological suppression, with 94% in group 1, 93% in group 2, 94% in group 3, and 100% in group 4 [24]. Among participants with viral titers less than 50 copies/mL at week 28 in groups 1 and 2, 94% in group 1 and 92% in group 2 maintained viral suppression at week 54 [24]. The primary endpoint was the percentage of participants with virological suppression (HIV-1 RNA < 50 copies/mL) at week 54, which was 90% in group 1, 85% in group 2, 85% in group 3, and 92% in group 4 [24]. By week 80, the percentage of participants with virological suppression was 87% in group 1, 75% in group 2, 87% in group 3, and 92% in group 4 [25]. At week 54, CD4 counts increased by a median of 219 cells per microliter among participants receiving LEN compared to 177 in those receiving BIC, emtricitabine, and tenofovir alafenamide [24]. At week 80, CD4 counts increased by a mean of 256 cells per microliter in groups 1–3 [25]. Three out of 157 participants developed resistance to LEN by week 80 [25]. The most common adverse events were injection-site reactions, headache, and nausea [24]. These results show that SQ LEN in combination with tenofovir alafenamide and BIC and oral LEN with emtricitabine and tenofovir alafenamide in treatment naïve participants with HIV maintained high rates of virological suppression up to week 80 of therapy [25].

4.2.3. CAPELLA

The Phase 2/3 CAPELLA trial is a randomized, quadruple-blind, placebo-controlled study that evaluated the antiviral activity of LEN when added-on to failing treatments in subjects with multi-drug resistant (MDR) HIV [26]. Subjects were divided into one of two cohorts. Criteria for inclusion in Cohort 1 consisted of subjects having stable viremia with an HIV-1 RNA of greater than 400 copies/mL during the screening period. Criteria for inclusion in Cohort 2 consisted of subjects with reduced viremia, HIV-1 RNA of less than 400 copies/mL during the screening period, or if they were enrolled in the trial after Cohort 1 had been filled [26]. In Cohorts 1A and 1B, subjects were administered 600 mg LEN tablet orally on days 1 and 2 and a 300 mg tablet on day 8 while continuing their current treatment; subjects in 1A received LEN tablets along with their failing therapy while the subjects in 1B received placebo tablets along with their failing therapy. Cohort 1A received subcutaneous LEN 927 mg on day 15 and then again 26 weeks after the first dose of subcutaneous LEN; along with their first dose of subcutaneous LEN, patients in Cohort 1A were also initiated on optimized background therapy. Cohort 1B received oral LEN and optimized background therapy on day 15 of the trial then were started on subcutaneous LEN later on. Subjects in Cohort 2 all received oral LEN and optimized background therapy starting from day 1 for 14 days before being transitioned to subcutaneous LEN on day 15 [26].

Of the 144 subjects who were initially screened, 72 subjects were enrolled in the trial. The primary outcome of the CAPELLA trial was to evaluate the percentage of participants in Cohort 1 who achieved a reduction of at least 0.5 log copies/mL in HIV-1 RNA levels from baseline through 14 days after their first dose of oral LEN [26]. 87.5% of subjects in Cohort 1 who received oral LEN achieved at least a 0.5 log copies/mL reduction in HIV-1 RNA levels while only 16.7% of subjects in Cohort 1 who received oral placebo achieved the same results [26]. One subject in Cohort two died during the study due to cancer. Therapy was well tolerated, with few instances of serious adverse effects and none being deemed attributable to LEN. The most common non-severe adverse effects were injection site related, while the most prominent non-severe adverse effects not-related to injection site reactions were constipation, diarrhea, nausea, and abdominal distension [26].

4.2.4. NCT05502341

NCT05502341 is an ongoing controlled study to evaluate the safety and efficacy of BIC/LEN versus current baseline therapy in virologically suppressed people with HIV-1 on stable complicated treatment regimens. NCT05502431 is an open-label, randomized, parallel-assignment, multicenter trial with two phases: phase 2 – BIC plus LEN verses current therapy and phase 3- BIC/LEN fixed-dose combination versus current therapy in people living with HIV. Participants must be on a stable baseline therapy that includes a complex combination antiretroviral regimen due to previous resistance or intolerance that includes a protease inhibitor or NRTI plus at least one other medication from any HIV drug class. Individuals on single tablet regimens or receiving a complete parenteral therapy were excluded. The phase 2 trial includes two experimental arms and an active comparator. All participants in the experimental arms initially completed a 2-day loading dose of 600mg LEN orally and were then randomized into one of two arms; arm 1 had participants switching from their stable baseline regimen to BIC 75mg plus LEN 25mg daily, while arm 2 had participants switching from their stable baseline regimen to BIC 75mg plus LEN 50mg daily. Participants in the active comparator arm maintained their current stable therapy. All participants were treated for at least 24 weeks in the randomized period and then were given the option to participate in an extension period to receive BIC/LEN fixed-dose combination. The primary outcome of the phase 2 trial is the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at week 24 based on the US FDA Snapshot Algorithm. The snapshot analysis algorithm is the currently recommended approach for the primary efficacy analysis for the HIV trials per FDA[27].

The Phase 3 component of NCT05502341 divides participants into an experimental arm and an active comparator. Participants in the experimental arm will switch from their stable baseline therapy to BIC/LEN fixed-dose combination (fixed dose based on data from week 24 date of phase 2 with participants receiving either BIC/LEN 75/25 or BIC/LEN 75/50) following a 2-day loading dose of LEN 600mg, and are treated daily for 48 weeks[28]. Participants in the active comparator will also continue to take their oral baseline therapy for 48 weeks. All participants will have the option to participate in the extension period to receive BIC plus LEN at the selected dose. The primary outcome of the phase 3 trial is the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at week 48 based on the US FDA Snapshot Algorithm[28]. Additionally, secondary outcomes are to determine changes in CD4 cell count from baseline and the percentage of participants experiencing adverse events due to treatment. Currently there are no results that have been published and no data has been reported.

4.3. Lenacapavir Resistance Profile

Lenacapavir establishes extensive hydrophobic and electrostatic interactions with capsid subunits 1 and 2 [29]. Substitutions to the capsid subunits results in changes in binding potential and the development of resistance [29]. Q67H and N74D capsid substitutions are the main resistance associated mutations (RAMs) that emerged in proximity to the LEN binding sites on capsid subunits [29]. When crosslinking capsid hexamers containing the Q67H substitution in the absence and presence of LEN, only the closed conformation was observed in the absence of LEN and both closed and open conformations were observed with the presence of LEN [29]. The closed His67 conformation sterically hinders LEN binding to the capsid subunits [29]. Upon LEN binding, the His67 side chain switches to the open conformation to accommodate for the LEN binding. This switch from the closed to open conformation results in a 5-fold reduced binding affinity and a 7-fold decreased potency. On the other hand, N74D substitutions on the capsid subunits introduces electrostatic repulsion to LEN binding [29]. This substitution affects the positioning of the sulfonamide group of LEN resulting in a more negative surface potential at this site and the loss of direct hydrogen bonding interaction [29]. As a result, the N74D substitution has a 20-fold decrease in LEN binding affinity to capsid hexamers and ~10-fold decrease in virus susceptibility to the inhibitor [29].

4.4. Pre-exposure prophylaxis Trials

4.4.1. PURPOSE

LEN by itself is also of high interest for pre-exposure prophylaxis for the risk of HIV-1 acquisition. The PURPOSE trials evaluated the safety and efficacy of twice-yearly LEN injection to prevent the risk of HIV[30]. PURPOSE 1 studies LEN in adolescent and young women while PURPOSE 2 studies LEN in cisgender men, transgender women, transgender men, and gender nonbinary people who have sex with male partners and are at risk of HIV infection[30].

The PURPOSE trials are ongoing phase 3, double blind, multicenter, randomized trials to study the efficacy and safety of twice-yearly subcutaneous injections of LEN and daily oral F/TAF- F/TDF as PrEP in people who are at high risk of HIV infection. There are four arms (a-d) of the PURPOSE trial. Following a two-day oral LEN lead-in, participants are divided between two experimental arms: (arm a) subcutaneous LEN injection every 26 weeks + placebo-to-match oral Emtricitabine/ Tenofovir (F/TAF for women and F/TDF for men) or (arm b) placebo LEN injections + oral Emtricitabine/Tenofovir for 52 weeks. Once the initial blinded 52 weeks are completed, all participants are eligible for (arm c) LEN open-label extension where all participants in the oral F/TDF (arm b) can opt-in to the LEN injection arm[30]. The final experimental group (arm d) allows all participants to be included in the PK Tail phase[30]. This phase includes a 26-week washout period from the last LEN injection to once daily oral dosing of F/TDF for 78 weeks. The primary endpoint is the HIV incidence reported per 100-person-years once participants have completed a minimum of 52 weeks of follow-up in the study. The secondary endpoints are (a) HIV Incidence among participants while adherent to LEN, (b) percentage of treatment-emergent adverse events among participants, and (c) percentage of participants experiencing clinically significant lab abnormalities[28]. Currently there are no results that have been published and no data reported.

5.0. Safety and Tolerability

5.1. Drug-Drug Interactions

5.1.1. Bictegravir Drug Interactions

Bictegravir inhibits organic cation transporter 2 (OCT2) and multidrug and toxic extrusion transporter 1 (MATE1). Co-administration with substrates of related transporters may experience increase in plasma concentrations [15,31]. BIC is a substrate and weak inhibitor of both P-glycoprotein and Breast Cancer Resistance Protein (BCRP). It is also a substrate of CYP3A and UGT1A1. Drugs that are inducers of CYP3A and UGT1A1 can reduce the therapeutic drug concentrations of BIC [31,32]. A list of clinically significant drug interactions associated with BIC is summarized in table 2 [31,32].

Table 2.

Drug-Drug interactions with bictegravir

Anticonvulsants Co-administration with anticonvulsants should be considered and monitored closely due to decrease therapeutic efficacy. [32]
Antimycobacterials Co-administration with Rifampin is contraindicated. Co-administration with Rifabutin or Rifapentine is not recommended. [32]
Herbal Products Co-administration with St. John’s Wort is not recommended. [32]
Polyvalent cations Co-administration with or 2 hours after antacids containing Al/Mg is not recommended. Co-administration with supplements or antacids containing Ca or Fe is recommended to be taken with food. [32]
Metformin Co-administration increased plasma concentrations of Metformin. [32]
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5.1.2. Lenacapavir Drug interactions

Lenacapavir is a substrate of cytochrome P450 (CYP)3A4, P glycoprotein (P-gp), and UGT1A1. [7] Medications that are strong or moderate inducers of CYP3A4 may decrease the concentration of LEN. The coadministration of these drugs with LEN is contraindicated. Additionally, it is not recommended to co-administer LEN with strong CYP3A, P-gp, and UGT1A1 inhibitors, as these may increase the plasma concentration of LEN.[7]

LEN is a moderate CYP3A4 inhibitor. It may increase concentration of medications by CYP3A4 substrates[7]. Clinical studies also demonstrate that LEN is an inhibitor of P-gp and BCRP. A list of clinically significant drug interactions associated with LEN is summarized (refer to table 3)

Table 3.

Drug-drug interactions with lenacapavir

Anticoagulants Co-administration increased effect of DOAC.
Refer to DOAC prescribing guidelines for anticoagulant use.		 [7]
Anticonvulsants Not recommended. Co-administration with anticonvulsants results in loss of therapeutic effect.
Co-administration with phenytoin is contraindicated.		 [7]
Antiretroviral Agents Not recommended. Co-administration with antiretroviral agents results in loss of therapeutic effect and development of drug resistance. [7]
Antimycobacterials Not recommended. Co-administration with antimycobacterials results in loss of therapeutic effect.
Co-administration with rifampin is contraindicated.		 [7]
Corticosteroids (systemic) Co-administration with corticosteroids increases exposures and risk of Cushing’s syndrome and adrenal suppression.
Start with lowest dose and monitor.		 [7]
Herbal Products Co-administration with St. John’s wort is contraindicated. [7]
HMG-CoA Reductase. Initiate lovastatin and simvastatin at lowest dose and monitor for potential myopathy. [7]
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5.2. Side Effect Profile

When both LEN and BIC based therapy is initiated in severely immunocompromised individuals, there is a risk of immune reconstitution syndrome (IRIS) occurring[7,15]. The most common adverse effects of oral LEN are nausea, constipation, and diarrhea [26]. When BIC is given as a monotherapy over a period of 10 days, the most common side effects are diarrhea and headache, but overall, it is well tolerated [20].

5.3. Regulatory Affairs

BIC was approved as a treatment for HIV as a combination with emtricitabine and tenofovir alafenamide in the United States by the FDA, as well as in the European Union by the European Medicines Agency in 2018 [15,32]. LEN was approved for both oral and subcutaneous use by the FDA and the European Medicines Agency in 2022 [7,17]. LEN plus BIC is currently undergoing Phases 2 and 3 clinical trials for use in people living with HIV[33].

6.0. Conclusions

In early clinical trials, the therapeutic combination of BIC/LEN, an INSTI and a HIV-1 capsid inhibitor, is well-tolerated and has been shown to be an effective therapy as a treatment for patients failing their current treatment for HIV-1 [20,23–25]. Current clinical trials are investigating LEN as either an oral or subcutaneous agent as part of a dual therapy for both treatment experienced and treatment naïve patients[24,25]. The combination has been shown to rapidly reach viral suppression in PLWH in an ongoing phase 2 trial [24,25,28]. An ongoing phase 3 trial to evaluate BIC/LEN versus current standard of care therapy has yet to publish any data or results [28]. The most common adverse effect for subcutaneous LEN is injection site reactions, and oral BIC and LEN are commonly associated with GI upset [17,32]. While this combination shows considerable promise for PLWH, especially for patients who have contraindications to NRTI based regimens, further investigational studies are necessary.

7.0. Expert opinion

7.1. Therapeutic Significance

Currently, most initial treatment regimens for PLWH utilize at least one nucleotide reverse transcript inhibitor (NRTI); many of these initial treatments are also oral triple therapies and require strict patient adherence daily to minimize the onset of resistance [11]. Adherence to antiretroviral therapy (ART) is one of the key determining factors in whether successful viral suppression occurs or if the development of drug-resistant HIV occurs [34]. If a patient is either non-adherent to their treatment or presents with an NRTI-resistant HIV infection, it can result in them needing more complex drug regimens and further increases the risk of non-adherence in patients. While resistance to NRTI medications is relatively slow to develop, development of resistance to NRTIs is detrimental considering that most first and second line ART regimens utilize at least one NRTI, and is associated with worsened disease outcomes [35]. Non-adherence can also be an issue for patients requiring NRTI-based treatments due to the complexity of some of the treatments or the side-effects associated with some of the medications. The approval of BIC/LEN as a therapy for newly diagnosed patients will be beneficial for patients who have contraindication to NRTI-based therapy. Some of the biggest concerns with NRTI medications include lactic acidosis and pancreatitis; in addition, many of the NRTI-based therapies increase the risk of renal insufficiency and may not be the best choice for patients with impaired renal function [11,36]. BIC and LEN both have mild side effect profiles and few restrictions for use, in comparison to NRTI-based therapy, and may be more favorable for promoting patient adherence.

7.2. Role for Resistant Treatment

Combination antiretroviral therapy has been used to treat HIV-1 infection by suppressing HIV-1 replication and increasing CD4 cell counts [37]. PLWH being treated with combination antiretroviral therapy can have life expectancy similar to those without HIV-1 [38]. However, this regimen requires strict adherence for the rest of a patient’s life to minimize the emergence of drug resistant variants. There has been an increase in HIV-1 site directed mutants and clinical isolates resistant to currently approved antiretrovirals [39]. Patients who are infected with HIV-1 multidrug-resistant viruses, or who have resistant virus evolve during their infection, have limited treatment options and are at increased risk of morbidity and mortality [40].

For patients with multidrug resistant HIV-1, the standard of care is dual therapy with agents with a high barrier of resistance or three fully active drugs if there is no fully active drug with high barrier of resistance [40]. The 2023 Department of Health and Human Services (DHHS) guidelines recommend using twice daily DTG or BIC and/or boosted DRV in patients with suspected drug resistance when no antiretroviral (ARV) history is available [11]. For patients who are experiencing treatment failure with ARV history and results from current and past resistance testing, the guidelines recommend DTG or BIC plus two NRTIs; boosted PI plus two NRTIs; or boosted PI plus INSTI [11]. BIC has a high resistance barrier to the development of HIV-1 resistance and is commonly used with the NRTI backbone to treat multidrug resistant HIV-1 [41]. For some patients, there are barriers that decrease the viability of NRTI-based regimens [42]. LEN/BIC will represent an important new therapeutic combination for the treatment of multidrug resistant HIV-1 with its well-tolerated side effect profile [7,15]. For patients receiving an initial ARV regimen with a high resistance barrier, the most common reason for treatment failure is nonadherence [40]. Within this niche, subcutaneous LEN in combination with oral BIC is likely to be able to become a significant player for patients to overcome barriers to adherence with its every 6 months dosing. One barrier to this treatment is that there are few other long-acting antiretrovirals, and the development of additional long-acting therapies will further improve patient care. There is a critical need for effective therapy in patients who have failed first line regimens and developed resistance to the NRTI backbone. Since LEN/BIC contains an agent with a new mechanism of action as a selective inhibitor of HIV-1 capsid protein, it is likely that a successful response will still occur even if partial resistance exists to one of the standards of care regimens. lenacapavir’s ability to maintain high rates of virological suppression will likely ensure that LEN/BIC will have a critical role in therapy for patients infected with HIV-1 in the years to come.

7.3. Long-Acting Dosing

Due to advancements in antiretroviral therapy (ART) people living with HIV have access to a variety of treatment options that can control their infection indefinitely [9]. A benefit of low frequency oral medication regimens means that patients with HIV only need to take a single-tablet regimen like the combination of tenofovir alafenamide, emtricitabine, and bictegravir, which includes the three drug classes recommended for initial treatment in treatment-naïve PWH. Benefits of multiple drug ART include reduction in treatment-related adverse events and toxicities, drug interactions, and cost [43]. Both dosing schedules increase the possibility of medication adherence. This is of importance because suboptimal ART adherence can promote HIV drug resistance and can complicate or limit future treatment options. Additionally, these dosing strategies can help with limiting unintended disclosure of HIV status, overall lower cost for treatment, and improve a person’s quality of life.

7.4. Place in therapy

Lenacapavir is the first medication in its class of capsid inhibitors. Currently it is recommended as an additional agent for patients who have failed their current therapy, primarily due to the development of resistance. The combination of LEN/BIC is likely to be beneficial for these patients, who could discontinue their failing therapy and instead start a single tablet regimen which is likely to be safe and effective for them. As it is a new medication, with little to no circulating resistance, at this point in time it should be reserved treatment experienced patients with few effective therapeutic options, rather than newly diagnosed individuals who can be effectively treated with other therapies.

Article Highlights.

  • Antiretroviral therapy for people living with HIV has radically evolved over time

  • Lenacapavir is a recently approved first in class capsid inhibitor which is currently approved for individuals with resistant virus who have failed other therapies

  • Lenacapavir is currently undergoing clinical trials in combination with the integrase inhibitor bictegravir for both treatment naïve and treatment experienced individuals

  • In ongoing clinical trials, this combination is both efficacious and well tolerated by individuals

  • As a first in class medication, use of lenacapavir with bictegravir should be limited to individuals who have failed other therapies, rather than be used for newly diagnosed individuals, due to an excellent resistance profile and limited therapeutic options for treatment experienced patients

Acknowledgements

We wish to thank Dr. Kirk Hevener for providing assistance with using the ChemDraw software.

Funding

This paper was funded by the National Institute of Health (Grant DA042374).

Footnotes

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

References

Papers of special note have been highlighted as either of interest (*) or of considerable interest (**) to readers.

  • [1].Sharp PM, Hahn BH. Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med. 2011. Sep;1(1):a006841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].HIV who.int: World Health Organization; 2023. [cited 2023 September 4th]. Available from: https://www.who.int/data/gho/data/themes/hiv-aids#:~:text=Globally%2C%2039.0%20million%20%5B33.1-,considerably%20between%20countries%20and%20regions.
  • [3].UNAIDS. Prevailing Against Pandemics: By Putting People At the Centre | World AIDS Day Report 2020. UNAIDS.org: United Nations; 2020. [Google Scholar]
  • [4].Pau AK, George JM. Antiretroviral therapy: current drugs. Infect Dis Clin North Am. 2014. Sep;28(3):371–402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. New England Journal of Medicine. 1987;317(4):185–191. [DOI] [PubMed] [Google Scholar]
  • [6].FDA Approves New HIV Drug for Adults with Limited Treatment Options [Internet]. FDA.gov: FDA; 2022; December 22nd, 2022. [cited September 4th, 2023]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-hiv-drug-adults-limited-treatment-options#:~:text=Sunlenca%20is%20the%20first%20of,approved%20for%20treating%20HIV%2D1. [Google Scholar]
  • [7].Sulenca (R) [Package insert] Gilead Sciences, Inc., Foster City, CA; 2022. [Google Scholar]
  • [8].Study to Compare Bictegravir/Lenacapavir Versus Current Therapy in People With HIV-1 Who Are Successfully Treated With a Complicated Regimen. [Google Scholar]
  • [9].Landovitz RJ, Scott H, Deeks SG. Prevention, treatment and cure of HIV infection. Nature Reviews Microbiology. 2023 2023/10/January;21(10):657–670. [DOI] [PubMed] [Google Scholar]
  • [10].Duncombe C, Ravishankar S, Zuniga JM. Fast-Track Cities: striving to end urban HIV epidemics by 2030. Current Opinion in HIV and AIDS. 2019;14(6):503–508. [DOI] [PubMed] [Google Scholar]
  • [11].Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. [Google Scholar]
  • [12].Global HIV Treatment Market Analysis Report 2023: A $25+ Billion Market by 2030 - Focus on Combination Therapies Gaining Momentum - ResearchAndMarkets.com 2023. [cited 2023 9/29]. Available from: https://www.businesswire.com/news/home/20230629675173/en/Global-HIV-Treatment-Market-Analysis-Report-2023-A-25-Billion-Market-by-2030---Focus-on-Combination-Therapies-Gaining-Momentum---ResearchAndMarkets.com
  • [13].Chun HM, Dirlikov E, Cox MH, et al. Vital signs: progress toward eliminating HIV as a global public health threat through scale-up of antiretroviral therapy and health system strengthening supported by the US President’s Emergency Plan for AIDS Relief—worldwide, 2004–2022. Morbidity and Mortality Weekly Report. 2023;72(12):317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].White KL, Osman N, Cuadra-Foy E, et al. Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes. Antimicrob Agents Chemother. 2023. May 1;65(5). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Biktarvy (R) [Package insert] Gilead Sciences, Inc, Foster City, CA; 2022. [Google Scholar]
  • [16].Link JO, Rhee MS, Tse WC, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020. Aug;584(7822):614–618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Sunlenca: European Unions Agencies Network; 2023. [updated June 27th, 2023; cited 2023 August 19th]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/sunlenca
  • [18].Zhang H, Custodio J, Wei X, et al. P176 Clinical pharmacology of the HIV integrase strand transfer inhibitor bictegravir. Sexually Transmitted Infections. 2017;93(Suppl 1):A74–A74. [Google Scholar]
  • [19].Podany AT, Scarsi KK, Pham MM, Fletcher CV. Comparative clinical pharmacokinetics and pharmacodynamics of HIV-1 integrase strand transfer inhibitors: an updated review. Clinical pharmacokinetics. 2020;59(9):1085–1107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Gallant JE, Thompson M, DeJesus E, et al. Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults. J Acquir Immune Defic Syndr. 2017. May 1;75(1):61–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Paik J Lenacapavir: First Approval. Drugs. 2022. Sep;82(14):1499–1504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Study to Evaluate Safety, Pharmacokinetics, and Antiviral Activity of Bictegravir (GS-9883) in Human Immunodeficiency Virus (HIV)-1 Infected Participants. [Google Scholar]
  • [23].Sax PE, DeJesus E, Crofoot G, et al. Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial. Lancet HIV. 2017. Apr;4(4):e154–e160. [DOI] [PubMed] [Google Scholar]
  • [24]*.Gupta SK, Berhe M, Crofoot G, et al. Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial. Lancet HIV. 2023. Jan;10(1):e15–e23. [DOI] [PubMed] [Google Scholar]
  • [25].Hagins DK E; Safran R; Santiago L; Wohlfeiler M; Hsiao C; Liu S; VanderVeen LA; Dvory-Sobol H; Rhee MS; Baeten J; Gupta S, editor Long-Acting Lenacapavir in a Combination Regimen for Treatment Naive PWH: Week 80 CROI; 2023; Seattle, WA. [Google Scholar]
  • [26]**. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2022. May 12;386(19):1793–1803. **This is a phase three trial which showed that adding lenacapavir to optimized background regimens increased viral suppression as compared to subjects who received a placebo.
  • [27].Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment (Guidance for Industry) In: Research CfDEa, editor. Silver Spring, MD: HHS; 2015. [Google Scholar]
  • [28].Study to Compare Bictegravir/Lenacapavir Versus Current Therapy in People With HIV-1 Who Are Successfully Treated With a Complicated Regimen Clinicaltrials.gov: NIH National Library of Medicine 2022. [cited 2023 9/10/2023]. Available from: https://classic.clinicaltrials.gov/ct2/show/record/NCT05502341?view=record [Google Scholar]
  • [29].Bester SM, Wei G, Zhao H, et al. Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science. 2020;370(6514):360–364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Study of Lenacapavir for HIV Pre-Exposure Prophylaxis in People Who Are at Risk for HIV Infection (PURPOSE 2) Clinicaltrials.gov 2022. [cited 2023 9/1/2023]. Available from: https://clinicaltrials.gov/study/NCT04925752 [Google Scholar]
  • [31].Subramanian R, Wang J, Murray B, et al. Human pharmacokinetics prediction with an in vitro-in vivo correction factor approach and in vitro drug-drug interaction profile of bictegravir, a potent integrase-strand transfer inhibitor component in approved biktarvy(®) for the treatment of HIV-1 infection. Xenobiotica. 2022. Dec;52(12):1020–1030. [DOI] [PubMed] [Google Scholar]
  • [32].Biktarvy [Website]. European Medicines Agency: European Union Agencies Network; 2023. [updated April 28th, 2023; cited 2023 August 19th]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/biktarvy#authorisation-details-section
  • [33].Study to Compare Bictegravir/Lenacapavir Versus Current Therapy in People With HIV-1 Who Are Successfully Treated With a Complicated Regimen [updated January]. Available from: https://classic.clinicaltrials.gov/show/NCT05502341 [Google Scholar]
  • [34].Martin M, Del Cacho E, Codina C, et al. Relationship between adherence level, type of the antiretroviral regimen, and plasma HIV type 1 RNA viral load: a prospective cohort study. AIDS research and human retroviruses. 2008;24(10):1263–1268. [DOI] [PubMed] [Google Scholar]
  • [35].Sluis-Cremer N, Wainberg MA, Schinazi RF. Resistance to reverse transcriptase inhibitors used in the treatment and prevention of HIV-1 infection. Future microbiology. 2015;10(11):1773–1782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Lesho EP, Gey DC. Managing issues related to antiretroviral therapy. American family physician. 2003;68(4):675–687. [PubMed] [Google Scholar]
  • [37].Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS. Lenacapavir: a first-in-class HIV-1 capsid inhibitor. Current Opinion in HIV and AIDS. 2022;17(1):15–21. [DOI] [PubMed] [Google Scholar]
  • [38]*. Teeraananchai S, Kerr S, Amin J, et al. Life expectancy of HIV-positive people after starting combination antiretroviral therapy: a meta-analysis. HIV medicine. 2017;18(4):256–266. *This is a study showing that lenacapavir has a high barrier for the development of resistance
  • [39].Margot N, Ram R, Rhee M, Callebaut C. Absence of lenacapavir (GS-6207) phenotypic resistance in HIV gag cleavage site mutants and in isolates with resistance to existing drug classes. Antimicrobial Agents and Chemotherapy. 2021;65(3): 10.1128/aac.02057-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Tang MW, Shafer RW. HIV-1 antiretroviral resistance: scientific principles and clinical applications. Drugs. 2012;72:e1–e25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Deeks ED. Bictegravir/emtricitabine/tenofovir alafenamide: a review in HIV-1 infection. Drugs. 2018;78:1817–1828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Holec AD, Mandal S, Prathipati PK, Destache CJ. Nucleotide reverse transcriptase inhibitors: a thorough review, present status and future perspective as HIV therapeutics. Current HIV research. 2017;15(6):411–421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [43].Santevecchi BA, Miller S, Childs-Kean LM. Doing More With Less: Review of dolutegravir-lamivudine, a novel single-tablet regimen for antiretroviral-naïve adults with HIV-1 infection. Annals of Pharmacotherapy. 2020;54(12):1252–1259. [DOI] [PubMed] [Google Scholar]

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