Updates in the Pipeline of HIV Therapy

BY DANIEL A. SOLOMON, MD, AND JONATHAN Z. LI, MD, MMSC

Modern antiretroviral therapy (ART) for HIV is well tolerated and highly effective. Most people with HIV (PWH) achieve virologic suppression with currently available options. So, where is the room for improvement? The recent advances in HIV therapy focus on new options for both treatment-naive and treatment-experienced patients, simplified drug regimens, and novel treatment strategies that do not rely on adherence to daily oral medication. In this article, we review the newest wave of ART, provide an update on 2-drug oral regimens, and discuss how treatment strategies may change with the approval of long-acting oral and injectable therapies.

The Most Exciting New Agents

Recently Approved by the FDA

Fostemsavir (FTR; Rukobia, ViiV Healthcare), the prodrug of temsavir, was approved in July 2020. FTR is a first-in-class glycoprotein 120 (gp120) attachment inhibitor that works by blocking viral attachment to the host CD4 cell. Compared with maraviroc (Selzentry, ViiV Healthcare), a CCR5 attachment inhibitor, it is active regardless of viral tropism, and there is no cross-resistance to any existing ART.1 The current role of FTR in HIV treatment is for patients with extensive antiviral resistance and limited therapeutic options. The BRIGHTE study was a phase 3 trial of patients experiencing virologic failure with multiclass resistance and no fully viable combination ART regimens available. When FTR was added to an optimized backbone for patients with 1 or 2 remaining active ART classes, 57% of individuals achieved a viral load less than 40 copies/mL at 48 weeks, compared with 45% in the placebo arm. For patients with no remaining antiretroviral options, 38% achieved a viral load less than 40 copies/mL at week 48, and participants demonstrated a mean increase in the CD4 cell count of 64 cells/mm3 . 2 FTR is an important addition to

the armamentarium of salvage therapy for patients with multiclass antiviral resistance.

Submitted for Approval by the FDA

Lenacapavir (LEN), developed by Gilead, is a highly potent, long-acting capsid inhibitor. Pharmacokinetic studies support subcutaneous injections every 6 months.3 Similar to FTR, as a first-in-class medication, this drug holds particular promise for patients with heavy treatment experience. In the CAPELLA study of patients with a long history of treatment with antiviral resistance (≤2 fully active agents from 4 main ART classes), the addition of subcutaneous LEN to an optimized backbone regimen led to virologic suppression in 81% of patients at week 26.4 Based on the preliminary data, in July 2021, Gilead submitted a New Drug Application to the FDA to be used for heavily treatment-experienced patients with multidrug-resistant (MDR) HIV.

Due to its novel mechanism of delivery, LEN also holds promise as a long-acting first-line therapy for treatment-naive patients, and as a long-acting agent for HIV pre-exposure prophylaxis (PrEP). In CALIBRATE, a phase 2 study of treatment-naive patients, individuals treated with subcutaneous LEN in addition to emtricitabine (FTC) and tenofovir alafenamide (TAF) achieved rates of viral suppression greater than 90% by week 16. The subcutaneous injection was generally well tolerated with no grade 3 or 4 adverse events (AEs) related to LEN. The most frequent AEs were local erythema, pain, or swelling at the injection site.5

In Development

Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor being developed by Merck, is an adenosine analog that acts as a reverse transcriptase chain terminator and prevents DNA translocation.6 A key feature of the medication is its prolonged half-life. As an oral medication, it may be an appealing strategy to decrease pill burden and is being tested as a oncemonthly oral agent in multiple phase 3 PrEP studies.7,8 Moreover, pharmacokinetic studies show that therapeutic levels of ISL can be sustained for longer than 6 months when the drug is administered by long-term drug-eluting implants.9 The implants hold promise for both HIV PrEP when used as monotherapy, and as treatment when used in combination with other medications. In a phase 1 study, the implant was found to be well tolerated and maintained adequate levels of ISL throughout the 12-week implantation period.10 The focus of the ISL drug development program also includes the evaluation of ISL-based 2-drug regimens, either as daily or weekly oral therapy, as reviewed later. Albuvirtide (ABT), which is being developed by Frontier Biotechnologies, is a novel fusion inhibitor that binds to the gp41 envelope protein, preventing HIV from fusing with the host cell membrane and entering the cell. Like the other medication in this class, enfuvirtide (Fuzeon, Genentech), it is administered by subcutaneous injection, but due to its prolonged half-life, it can be given just once weekly. Currently, the target population for this medication is people with multiclass resistance or intolerance of multiple classes of medications. The TALENT study is a phase 3 trial comparing ritonavir-boosted lopinavir plus either ABT or 2 nucleoside reverse transcriptase inhibitors (NRTIs) (second-line treatment recommended by the World Health Organization) in treatment-experienced participants in China experiencing virologic failure. An interim analysis at week 48 found that 80% of patients in the ABT arm had a viral load less than 50 copies/mL compared with 66% in the NRTI arm.11 ABT is approved for second-line therapy in China where access to alternative oral medications, like integrase strand transfer inhibitors (INSTIs), may be more limited.

Maintenance therapy for individuals with good virologic control is another potential use for ABT when combined with other agents. There are ongoing phase 2 studies of ABT plus 3BNC117 (a broadly neutralizing antibody) either as long-acting maintenance therapy in virologically suppressed patients12 or for those with MDR HIV.13

Promising Daily Oral 2-Drug Regimens

Long-held dogma that effective ART must consist of 3 active antiretrovirals has been challenged by several recent studies suggesting that 2-drug therapy may be adequate for selected combinations. Two single-tablet, 2-drug regimens have been approved, and other combinations of oral medications are under investigation.

Approved Combinations

Combination dolutegravir-rilpivirine (DTG/RPV; Juluca, ViiV Healthcare), approved in November 2017, was the first complete single-tablet regimen consisting of only 2 drugs. The combination has proven effective as a switch regimen in treatment-experienced patients who are virologically suppressed. In 2 identical phase 3, open-label trials, SWORD-1 and SWORD-2, treatment-experienced participants without non-NRTI (NNRTI) resistance and with good virologic control were randomly assigned to switch to DTG/RPV or remain on their current ART. Participants who were switched to DTG/RPV maintained virologic

suppression at 48 weeks, and experienced fewer AEs with better renal and bone outcomes than participants who remained on their current ART.14 Multiple observational studies have confirmed that patients maintain durable virologic suppression after switching to DTG/RPV.15,16

Coformulated DTG/RPV is a promising NRTI-sparing regimen for patients with side effects to current ART, contraindications to NRTIs, or who are just looking for regimen simplification. It is a particularly good option for patients with renal impairment, as exposure to DTG and RPV is not affected by decreased renal function. This combination has only been studied as a switch regimen in patients who are already virologically suppressed with no history of treatment failure or major drug resistance, and has not been assessed in treatment-naive individuals.

Coformulated DTG-lamivudine (DTG/3TC; Dovato, ViiV Healthcare) was approved in April 2019, making it the second complete regimen consisting of a single-tablet, 2-drug combination. In contrast to DTG/RPV, DTG/3TC has proven effective as initial therapy in treatment-naive individuals. GEMINI-1 and GEMINI-2 were identically designed large phase 3 studies comparing the 2-drug regimen of DTG/3TC with the 3-drug regimen DTG/FTC/tenofovir disoproxil fumarate (TDF) in ART-naive participants. At week 48, the 2-drug regimen was found to be noninferior to the 3-drug regimen, with fewer AEs. Of note, DTG/3TC was not associated with emergence of treatment-associated mutations.17 Multiple switch studies have demonstrated maintenance of viral suppression when patients with virologic control are transitioned to DTG/3TC, including a large phase 3 switch study called TANGO, which showed that DTG/3TC was noninferior in maintaining virologic suppression compared with TAF-

Recent advances in based regimens.18-21 DTG/3TC is the first 2-drug regimen to be

HIV therapy focus on included as an option for treatment-naive individuals with a baseline viral load less than new options for both 500,000 copies/mL in the National Institutes of Health HIV/AIDS treatment guidetreatment-naive and lines.22 Because tenofovir is not included in the regimen, hepatitis B coinfection is a contreatment-experienced traindication to this 2-drug regimen. patients, simplifi ed Under Investigation Two-drug therapy is a focus of the ISL drug regimens, and drug development program. The combination that is farthest along in clinical triimproved adherence. als is ISL-doravirine (DOR), a highly potent NNRTI with a distinct resistance pathway from earlier generation NNRTIs. In a phase 2 clinical trial, DRIVE2SIMPLIFY, treatmentnaive patients underwent a 24-week leadin period with ISL/DOR/3TC. Participants who were then simplified to the daily 2-drug regimen ISL/DOR maintained high rates of virologic suppression.23 Preliminary results from 2 phase 3 switch studies also reported that daily treatment with the combination once-daily regimen of ISL/DOR maintained virologic suppression.24 ISL/DOR is also being evaluated in phase 3 studies of treatment-naive25 and treatment-experienced PWH.26 In addition, leveraging the long half-life of oral ISL, a dose-ranging study for once-weekly ART with ISL plus MK8507, a novel NNRTI also being developed by Merck, is underway,27 as is a phase 2 switch study of weekly oral ISL with oral LEN in PWH with virologic suppression.28

Long-Acting Injectable Therapy

Long-acting injectable ART has been on the horizon for several years and holds promise as a paradigm shift for HIV treatment. Similar to monthly injections of other medications such as the contraceptive medroxyprogesterone acetate (Depo-Provera, Pfizer), long-acting injectable ART would preclude the need for daily oral medications. After a prolonged wait, Cabenuva, a monthly injection of cabotegravir (CAB; ViiV Healthcare), a novel INSTI, and RPV (Edurant, Janssen) were approved by the FDA in January 2021 for patients who are virologically suppressed on a stable ART regimen with no history of treatment failure and no known or suspected resistance to either CAB

or RPV. Patients are instructed to first switch to an oral formulation of CAB (Vocabria, ViiV Healthcare) and RPV for 1 month to assess tolerability before starting long-acting CAB/RPV.

CAB/RPV has been studied in both treatment-naive and treatment-experienced individuals. The FLAIR trial included treatment-naive patients who were all given a 20-week period of oral DTG/abacavir/3TC. Participants who achieved virologic suppression after the oral lead-in period were randomized to continue the oral regimen or switch to monthly CAB/RPV injections. Using the primary end point of HIV-1 RNA viral load of no more than 50 copies/mL HIV-1 RNA, switching to CAB/RPV was found to be noninferior to continuing oral treatment. At week 48, 2.1% of patients in the long-acting injectable arm had HIV-1 RNA of no more than 50 copies/mL, compared with 2.5% of patients who continued oral therapy.29 Of note, individuals randomized to the switch arm first received oral CAB/RPV for 4 weeks to assess tolerability before starting the injections.

The ATLAS trial included treatment-experienced patients with virologic control and no baseline NNRTI or INSTI resistance who were randomized to remain on their current oral therapy or switch to monthly injections of CAB/RPV. In a similar outcome to the FLAIR trial, the long-acting injectable arm was noninferior at week 48, with 1.6% of participants found to have HIV-1 RNA of at least 50 copies/mL compared with 1.0% in the oral arm.30

The medication is administered every 4 weeks, but in ATLAS-2M, a recently published phase 3b study, rates of virologic suppression were noninferior when doses were administered every 8 weeks compared with every 4 weeks in a week 96 analysis.31

Injectable CAB/RPV also may shift the paradigm for HIV PrEP. Multiple studies have demonstrated that the injection is safe and well tolerated in HIV-uninfected individuals.32,33 Two paired studies, HPTN 083 (which enrolled cisgender men and transgender women who have sex with men) and HPTN 084 (which enrolled cisgender women in sub-Saharan Africa), compared the efficacy of CAB injections with oral TDF/FTC for PrEP. Both studies were stopped early by the data safety monitoring board when long-acting CAB administered every 8 weeks was found to be statistically superior to daily oral TDF/FTC.34,35

Conclusion

In 2021, most patients with HIV who are engaged in care are virologically suppressed, but advances have led to simplified regimens, decreased cumulative drug exposure, and expanded therapeutic options for patients with multiclass resistance. The field continues to evolve with the recent approval of the first long-acting injectable combination, as well as drugs from novel classes and drug-eluting implants on the horizon.

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About the authors

Daniel A. Solomon, MD, is an infectious disease specialist with the Division of Infectious Diseases at Brigham and Women’s Hospital; and an instructor of medicine at Harvard Medical School, in Boston, Massachusetts.

Jonathan Z. Li, MD, MMSc, is an infectious disease specialist with the Division of Infectious Diseases at Brigham and Women’s Hospital; and an associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.