Although advances in combination antiretroviral therapy (ART) have greatly reduced morbidity and mortality associated with HIV, the pipeline for development of novel drug mechanisms and new agents in the existing drug classes remains full. This article presents a review of investigational drugs furthest along in development with propitious results in human subjects.
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NRTI)
GS-9131 is a prodrug of the nucleotide analogue GS-9148.1
It inhibits reverse transcription by chain termination. GS-9131 was shown to have broad in vitro activity against HIV-1 and HIV-2 and was not significantly affected by the presence of reverse transcriptase mutations K65R, L74V, M184V, or their combinations.1
In vitro resistance selection studies have shown a high barrier to resistance.1
GS-9131 has low potential for mitochondrial toxicity and renal accumulation.2
It is a promising candidate with once-daily dosing in combination with other ART in patients with NRTI resistance and limited treatment options.
NUCLEOSIDE REVERSE TRANSCRIPTASE TRANSLOCATION INHIBITOR (NRTTI)
MK-8591 (EFdA) is an adenosine analogue that both acts as a reverse transcriptase chain terminator and prevents DNA translocation.3
It has a prolonged half-life of 150 to 160 hours.4
In early clinical studies, single oral doses of 0.5 to 30 mg of MK-8591 resulted in >1.2- log viral load decline by day 7. This suggests the NRTTI’s potential for once-weekly dosing, with high potency, at a very low dose.5
However, because of its high intrinsic aqueous solubility, an injectable formulation is not considered feasible.5
Studies in rat models using nondegradable polymer implants have shown a plasma half-life of up to 100 days, so the possibility of human implants with a dosing interval of 1 year or longer is being explored.6
Initial pharmacokinetic data show that inhibitory quotients of MK-8591 for both wild-type and NRTI-resistant HIV-1 at low once-daily and once-weekly doses are substantially higher than those of any currently approved NRTIs.7
Common NRTI mutations, including M1841/V, thymidine analogue mutations, K65R, and K70E, confer just low-fold shifts in antiviral potency of MK-8591.7
Currently, a phase 2b clinical trial is under way to test MK-8591 for the treatment of HIV-1 infection with once-daily administration of 0.25, 0.75, or 2.25 mg in combination with doravirine.8
In addition, no clinically meaningful effect on the pharmacokinetics of MK-8591 was observed when coadministered with dolutegravir and tenofovir.9
In a prevention study in animals, weekly oral dosing of MK-8591 completely protected rhesus macaques from repeated rectal HIV challenges.10
These findings raise the possibility of exploring the use of MK-8591 administered as a long-term implant for both treatment and prevention of HIV infection.
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI)
Elsulfavirine (VM1500A) is a long-acting NNRTI with a half-life that allows for once-weekly dosing. A phase 2b clinical trial tested Elpida (a prodrug of elsulfavirine) at a dose of 20 mg orally once daily against efavirenz, both in combination with tenofovir disoproxil fumarate/emtricitabine in treatment-naïve patients living with HIV.11
Viral suppression was attained in 81% of Elpida recipients compared with 74% in the efavirenz arm. A higher response rate was noted in Elpida recipients with a baseline viral load of >100,000 copies/mL (78% vs 68%). No virologic failure (defined as 2 consecutive HIV RNA plasma levels of >400 copies/mL) was experienced. Drug-related adverse effects (AEs) were about half as frequent in the Elpida group compared with the efavirenz group (36.7% vs 77.6%, respectively).
Elsulfavirine received its first global approval in Russia in June 2017. Given its excellent tolerability and long half-life, its developer, Viriom, initiated a phase 1b clinical trial of once-weekly oral dosing of elsulfavirine (Elida, VM1500) in 36 HIV-uninfected volunteers for an 8-week treatment period in Moscow. Participants were randomized to a 40-, 80-, or 160-mg treatment group.12
A phase 2a trial of once-weekly oral elsulfavirine in combination with other antiretroviral agents in patients infected with HIV is now being planned by Viriom.12
Preclinical pharmacokinetic studies have also shown the potential of VM1500A nano suspensions for developing long-acting injectable formulations.13
INTEGRASE STRAND TRANSFER INHIBITOR (INSTI)
Cabotegravir is an INSTI with a structure and resistance profile similar to that of dolutegravir.4
Its availability in nano formulation with a half-life of 21 to 50 days4 makes it an option for monthly or bimonthly parenteral administration. Results from 2 phase 3 trials are now available. The ATLAS (Antiretroviral Therapy as Long-Acting Suppression) study evaluated monthly injectable cabotegravir plus rilpivirine in 616 treatment-experienced people who switched from a standard oral antiretroviral combination with an undetectable viral load to injectable cabotegravir plus rilpivirine. The injectable formulation was found to be noninferior to continued oral therapy.14
The FLAIR (First Long-Acting Injectable Regimen) study tested the injectable formulation of cabotegravir plus rilpivirine in treatment-naïve individuals. Patients were first started on induction dolutegravir/abacavir/ lamivudine for 20 weeks and then randomized to either continued oral therapy or switched to injectable cabotegravir plus rilpivirine. Virological success rates were 93.3% in the continued oral therapy group versus 93.6% in the injectable group.15
Injection site reactions, predominantly pain, were noted in 20% to 30% of participants. Both studies had 3 individuals, each with virological failure (defined as HIV-1 RNA ≥200c/ mL in consecutive samples). All individuals had HIV subtype A virus with evidence of mutations in the NNRTI and INSTI domains.14,15
In assessing patient satisfaction with injectable formulations, many patients were found to prefer monthly injections over daily oral medications.
Long-acting injectable cabotegravir is also being evaluated for pre-exposure prophylaxis in HIV-uninfected individuals.
CD4 ATTACHMENT INHIBITOR
Fostemsavir targets the first step of HIV entry by binding HIV envelope glycoprotein 120, thus inhibiting the virus from binding to the CD4 receptor.16
It is first in its class, thus offering an option for individuals with highly drug-resistant HIV. It is an oral prodrug of temsavir17
and can be dosed once daily. Twelve percent of participants in a phase 1 trial had baseline envelope polymorphisms that lowered susceptibility to fostemsavir.4
This raises the issue of the need for patient screening for polymorphisms prior to therapy. Based on encouraging efficacy results and good tolerability obtained in phase 2 studies, the ongoing BRIGHTE phase 3 study17
is evaluating the utility of fostemsavir as a salvage therapy with an optimized background regimen (OBR) in individuals failing ART. Initial results at 48 weeks have shown a 0.8 log copies/ml drop (about a 6.5-fold drop) in viral load compared with an 0.2 log drop in those on placebo with OBR. These results support the further development of fostemsavir as a therapeutic option for HIV-1-infected, highly treatment-experienced with multidrug resistance.
Leronlimab (PRO 140) is a humanized IgG4 monoclonal antibody that blocks the CCR5 coreceptor.18
It does not appear to interfere with the normal function of CCR5 in mediating immune responses. Weekly subcutaneous injections resulted in ≥1.65 log10 mean viral load reduction when tested as a single agent maintenance therapy after initial ART.18
A 92% response rate was seen at a 700-mg dose in a phase 3 trial.19
Patients who failed to respond to leronlimab safely achieved viral suppression upon resuming the ART regimens they maintained prior to enrollment.19
Cenicriviroc (CVC) is another CCR5 antagonist. It also has an inhibitory effect on CCR2.20
This additional anti-inflammatory effect may lead to an improvement in HIV-associated neurocognitive impairment21
by reducing monocyte immune activation. Phase 2b study22
results showed noninferiority and better tolerability compared with efavirenz when coadministered with tenofovir/emtricitabine.20
A phase 3 clinical trial is already under way to evaluate its role in the treatment of nonalcoholic steatohepatitis, and a phase 3 clinical trial is being planned to investigate a fixed-dose combination ART tablet containing cenicriviroc plus lamivudine.
Albuvirtide is a long-acting injectable fusion inhibitor that inhibits HIV virus from entering CD4 cells by attaching to an envelope glycoprotein, gp41, on the outer surface of HIV.23
It was tested in the Test Albuvirtide in Experienced Patients (TALENT) study,24
the first phase 3 licensing study of a new antiretroviral drug conducted in China, where it was approved in 2018.
Investigators randomized 389 treatment-experienced individuals with virological failure on a first-line regimen to receive either a weekly infusion of albuvirtide (dose unspecified) plus twice-daily dosing of the boosted protease inhibitor lopinavir/ritonavir or a regimen of lopinavir/ritonavir twice daily plus 2 NRTIs: lamivudine and either tenofovir, abacavir, or zidovudine, depending on previous treatment history (72% received tenofovir; 26%, zidovudine; 1%, abacavir; and 1%, tenofovir and zidovudine). At 48 weeks, 80.4% of the albuvirtide group had a viral load below 50 copies/mL by intent-to-treat analysis compared with 66% in the triple-drug group. The albuvirtide arm was noninferior to the standard triple-drug regimen in second-line treatment. No resistance to albuvirtide was detected, and it was well tolerated.
A US phase 2 multicenter, 3-part study was initiated in October 2018 to establish the dosage, safety, and antiviral activity of combination therapy with albuvirtide and 3BNC117 (a broadly neutralizing antibody) as long-acting maintenance therapy in virologically suppressed subjects with HIV-1 infection.25
GS-CA1 is the first capsid inhibitor to enter preclinical studies. The capsid is a cone-shaped structure that encloses the viral genome and is vital to HIV replication. GS-CA1 interferes with the disassembly of the capsid protein and transport of viral genetic material into the host cell nucleus. It also interferes with the assembly of capsids of the newly produced virus, resulting in immature viral particles unable to infect new cells. It is a highly potent inhibitor of HIV-1 replication in T-cell lines (EC50 = 0.24nM), with full activity against HIV-1 mutants resistant to licensed antiretroviral drugs. It has shown high in vitro metabolic stability, low systemic drug clearance, and a long half-life (7.2-18.7 hours). Its low aqueous solubility allows for an extended-release preclinical pharmacokinetic profile after subcutaneous administration of a solid depot formulation.26
GS-6207 is a modified version of GS-CA1. A first human study showed that a single subcutaneous injection of GS-6207 resulted in sustained concentrations for at least 24 weeks. The sustained delivery pharmacokinetic profile of a subcutaneous formulation may allow for a 3-monthly dosing interval. Safety data are still blinded; however, no serious AEs or deaths have been noted.27
Based on these findings, a proof-of-concept study is under way to determine the optimal dose and frequency of administration in HIV-infected individuals. Efforts are also being made to develop an oral formulation of GS-6207.
ABX464 is an orally available small molecule that stops viral replication by interfering with the activity of Rev, an HIV protein essential for making RNA strands. Exposure to ABX464, therefore, produces shorter RNA fragments, rendering them useless to produce new viruses. Small peptides produced by these RNA fragments alert the immune system, which can then eliminate the HIV-infected cells. This may help reduce the reservoir of HIV DNA in the body, with the hopes of achieving a “functional cure” without the need for lifelong treatment.28
Reductions of greater than 25% in integrated HIV DNA (HIV DNA most likely to lead to HIV replication) were observed in 41% of individuals in the ABX464 arm of a phase 2a randomized trial.29
Viral rebound, however, was noted with treatment interruption. Viral load reduction >0.5 log was observed in 1 of 6 HIV treatment-naïve patients in the 75-mg cohort, 2 of 6 in the 100-mg cohort, and 4 of 6 in the 150-mg cohort. ABX464 was well tolerated in this first study in HIV-infected patients.
Akram is an infectious diseases fellow at Thomas Jefferson University, Philadelphia, Pennsylvania. Her areas of interest include longitudinal care of HIV patients, and she is working on a site-specific screening project for sexually transmitted infections in HIV patients. She is a member of the Infectious Diseases Society of America.
DeSimone is a professor of medicine at Sidney Kimmel Medical College, Thomas Jefferson University, where he is also the program director for the infectious diseases fellowship. His area of special interest is in HIV care.
1. White K, Margot N, Stray K, et al. GS-9131 is a novel NRTI with activity against NRTI-resistant HIV-1. Conference on Retroviruses and Opportunistic Infections;
February 13-16, 2017; Seattle, Washington. Abstract 436.
2. Cihlar T, Laflamme G, Fisher R, et al. Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob Agents Chemother
. 2009 Jan;53(1):150-6. doi: 10.1128/AAC.01183-08.
3. Michailidis E, Marchand B, Kodama EN, et al. Mechanism of inhibition of HIV-1 reverse transcriptase by 4’-Ethynyl-2-fluoro-2’-deoxyadenosine triphosphate, a translocation-defective reverse transcriptase inhibitor. J Biol Chem
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4. Gulick PM. Investigational Antiretroviral Drugs: What is coming down the pipeline. Top Antivir Med
. 2018 Apr;25(4):127-132.
5. Barrett SE, Teller RS, Forster SP, et al. Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV treatment and Prevention. Antimicrob Agents Chemother
. 2018 Sep 24;62(10). pii: e01058-18. doi: 10.1128/AAC.01058-18.
6. Flexner C. Antiretroviral implants for treatment and prevention of HIV infection. Curr Opin HIV AIDS.
2018 Jul;13(4):374-380. doi: 10.1097/COH.0000000000000470.
7. Grobler J, FIllgrove K, Hazuda D, et al. MK-8591 potency and PK provide high inhibitory quotients at low doses QD and QW. Conference on Retroviruses and Opportunistic Infections
; March 1-7, 2019; Seattle, Washington. Abstract 481
8. Rudd DJ, Zhang S, Fillgrove KL, et al. Pharmacokinetics of MK-8591, Dolutegravir and Tenofovir Disoproxil Fumarate are not altered after coadministration when compared to single agent administration. International Congress on Drug Therapy in HIV Infection (HIV Glasgow);
October 28-31, 2018; Glasgow, Scotland. Poster 025
9. ClinicalTrials.gov. MK-8591 with doravirine and lamivudine in participants infected with human immunodeficiency virus type 1 (MK-8591-011) (DRIVE2Simplify). http://clinicaltrials.gov/ct2/show/NCT03272347
. Accessed on April 23, 2019.
10. Markowitz M, Gettie A, St. Bernard L, et al. Low dose MK-8591 protects rhesus macaques against rectal SHIV infection. Conference on Retroviruses and Opportunistic Infections;
March 4-7 2018; Boston, Massachusetts. Abstract 89LB
11. Murphy R, Kravchenko A, Orlova-Morozova E, et al. Elsufavirine as compared to efavirenz in combination with TDF/FTC: 48-week study. Conference on Retroviruses and Opportunistic Infections;
February 13-16, 2017; Seattle, Washington. Abstract 452 LB.
12. ClinicalTrials.gov. Phase Ib Study of Safety, Tolerability and Pharmacokinetics of Elpida Once Weekly in Healthy Volunteers. https://clinicaltrials.gov/ct2/show/NCT03730311. Accessed on April 23, 2019.
13. Bichko V, Rogovoy B, Koryakova A, et al. Pre-clinical pharmacokinetics of elsufavirine/VM1500A long acting injectable formulations. International Antiviral Society-USA.
2017. Poster WEPEA0190.
14. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir + rilpivrine as maintenance therapy: ATLAS week 48 results. Conference on Retroviruses and Opportunistic Infections
; March 1-7, 2019; Seattle, Washington. Abstract 139.
15. Orkin C, Araste’h K, Go’rgolas M, et al. Long-acting cabotegravir + rilpivrine for HIV maintenance: FLAIR 48 weeks results. Conference on Retroviruses and Opportunistic Infections
; March 1-7, 2019; Seattle, Washington. Abstract 140.
16. Cahn P, Fink V, Patterson P. Fostemsavir: a new CD4 attachment inhibitor. Curr Opin HIV AIDS
. 2018 Jul;13(4):341-345. doi: 10.1097/COH.0000000000000469.
17. Ackerman P, et al. Week 48 safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment experienced participants (BRIGHTE study). International Congress on Drug Therapy in HIV Infection (HIV Glasgow);
October 28-31, 2018; Glasgow, Scotland. Abstract O344A.
18. Lalezari J, Dhody K, Kowalczyk U, et al. PRO140 single agent maintenance therapy for HIV-1 infection: A 2 year update. Conference on Retroviruses and Opportunistic Infections;
February 13-16, 2017; Seattle, Washington. Abstract 437.
19. ClinicalTrials.gov. A Randomized, Double-blind, Placebo-controlled Trial, Followed by Single-arm Treatment of PRO 140 in Combination w/ Optimized Background Therapy in Treatment-Experienced HIV Subjects (PRO 140). https://clinicaltrials.gov/ct2/show/record/NCT02483078. Accessed on April 23, 2019.
20. Thompson M, Saag M, DeJesus E, et al. A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatment-naive HIV-infected adults with C-C chemokine receptor type 5-tropic virus. AIDS
. 2016 Mar 27;30(6):869-78. doi: 10.1097/QAD.0000000000000988.
21. ClinicalTrials.gov. Effect of Cenicriviroc on HIV Neurocognitive Impairment. https://clinicaltrials.gov/ct2/show/NCT02128828. Accessed on April 23, 2019.
22. ClinicalTrials.gov. Efficacy, Safety, and Tolerability of Cenicriviroc (CVC) in Combination With Truvada or Sustiva Plus Truvada in HIV 1-infected, Antiretroviral Treatment-naïve, Adult Patients Infected With Only CCR5-tropic Virus. https://clinicaltrials.gov/ct2/show/study/NCT01338883. Accessed on April 23, 2019.
23. Chong H, Yao X, Zhang C, et al. Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid-modified peptide fusion inhibitor. PLoS ONE
. 2012;7(3):e32599. doi: 10.1371/journal.pone.0032599.
24. Wu H et al. Efficacy and safety of long-acting HIV fusion inhibitor albuvirtide in antiretroviral- experienced adults with HIV-1: interim 48-week results from the randomised, controlled, phase 3, non-inferiority TALENT study. Glasgow Congress on HIV Therapy
; October 23-26, 2016; Glasgow, Scotland. Oral abstract O336. Webcast: https://vimeo.com/189136480.
25. ClinicalTrials.gov. Albuvirtide and 3BNC117 as Long-Acting Maintenance Therapy in Virologically Suppressed Subjects (ABL). https://clinicaltrials.gov/ct2/show/NCT03719664. Accessed on April 24, 2019.
26. Tse WC, Link JO, Mulato A, et al. Discovery of novel potent HIV capsid inhibitors with long-acting potential. Conference on Retroviruses and Opportunistic Infections;
February 13-16, 2017; Seattle, Washington. Abstract 38.
27. Sager JE, Begley R, Rhee M, et al. Safety and PK of subcutaneous GS-6207, a novel HIV-1 capsid inhibitor. Conference on Retroviruses and Opportunistic Infections
; March 1-7, 2019; Seattle, Washington. Abstract 14.
28. Vandekerckhove L, et al. ABX464 decreases total HIV DNA in PBMCs when administered during 28 days to HIV-infected patients who are virologically suppressed. 16th European AIDS
; October 25-27, 2017; Milan, Italy. Abstract PS 1/7.
29. Rutsaert S, Steens JM, Gineste P, et al. Safety, tolerability and impact on viral reservoirs of the addition to antiretroviral therapy of ABX464, an investigational antiviral drug, in individuals living with HIV-1: a Phase IIa randomised controlled study. J Virus Erad
. 2019 Jan 1;5(1):10-22.