New Initiatives for HIV Taking Off This Year

Advancements in the management of HIV over the past several decades have led to remarkable improvements in patient survival and quality of life. Yet, disparities in diagnosis, retention in care, and treatment failure continue to hinder the goal of disease eradication, hence propelling new initiatives. A multifaceted approach to global HIV control now routinely involves such strategies as pre-exposure prophylaxis (PrEP) in high-risk populations, widespread screening, treatment as prevention, and ongoing efforts to dispel the stigma of living with the disease. Maximizing antiretroviral (ARV) potency, convenience, and tolerability is another constantly moving target. In 2017, significant progress in HIV treatment was achieved with approval of the first 2-drug maintenance regimen for select patients with HIV and the early clinical success of long-acting injectable therapy. Additional October 2017 adult and adolescent ARV guideline updates by the US Department of Health and Human Services (DHHS) for implementation into clinical practice are listed in Table.¹

REGIMEN SIMPLIFICATION—WILL TWO DO?

Since the advent of combination antiretroviral therapy (cART) in the early 1990s, standard HIV regimens consist of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a third agent from a different therapeutic class to maximize antiviral efficacy. However, as patients now initiate treatment earlier and live longer, they also become more vulnerable to long-term medication toxicities. This has led to a re-emerging interest in simplified, drug-sparing regimens.² Secondary benefits of these regimens may include antiretroviral therapy (ART) preservation, improved convenience, fewer drug interactions, and reduced costs.

In November 2017, the US Food and Drug Administration approved the first 2-drug regimen to treat HIV.³ Juluca is a fixed-dose regimen that contains the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) and the non-nucleoside reverse transcriptase inhibitor rilpivirine (RPV).⁴ This is the first complete single-tablet regimen that does not incorporate NRTIs, thus sparing patients potential toxicity from these agents. Clinical use of this regimen likely preceded its formal approval, as published data of real-world application populates the literature.^5,6

The data behind the approval of this regimen come from 2 open-label, multicenter phase 3 clinical trials, SWORD 1 and SWORD 2, presented at the 2017 Conference on Retroviruses and Opportunistic Infections.⁷ All patients (N = 1024) enrolled in this study were suppressed, with HIV-1 RNA <50 cells/ mL for at least 12 months with no history of virologic failure. Patients either continued their cART suppressive regimen or switched to DTG / RPV. Results demonstrated noninferiority of viral suppression for the 2-drug regimen at 48 weeks compared with traditional 3- or 4-drug regimens.

DTG / RPV does not necessarily translate into success of all simplified regimens. Other published attempts at 1- or 2-drug regimens produced varying results or unclear applicability.² A prime example was the initial promise of DTG monotherapy. However, in a randomized trial comparing DTG with cART in virologically suppressed patients, several patients experienced virologic failure with DTG alone, prompting premature study discontinuation.8 Subsequently, phase 1 investigation of DTG with lamivudine has shown greater promise in select virologically suppressed patients, although further study is needed.⁹

THE FORMULATION FRONTIER—LONG-ACTING ART

Despite a multitude of available fixed-dose regimens, adherence to daily lifelong ART still challenges many patients. The development of long-acting (LA) ARVs to facilitate HIV treatment and prevention seems intuitive and mimics modern approaches to many other chronic disease states. Transdermal, injectable, and implantable drug delivery options may reduce pill fatigue and thus improve adherence, overcome oral bioavailability concerns, and potentially expand options for medication access. In a study of patient attitudes toward LA ARVs, 84% of patients indicated they would “definitely” or “probably” try injectable therapy offered on a monthly basis.¹⁰ Although properties such as aqueous solubility, metabolism, elimination, and dosing volume limit the repertoire of potential injectables, several ARVs have recently entered advanced clinical study for emerging use. Physiologically based pharmacokinetic modelling simulations have been applied and validated to identify and characterize candidate drugs.¹¹ Most favorable at this time is the novel combination of cabotegravir (GSK1265744; CAB) and RPV, 2 ARVs with physiochemical compatibility, yet unique mechanisms of action that lack significant pharmacokinetic interactions.^12,13

CAB, an experimental INSTI and DTG analogue, was first evaluated as an oral tablet and later as an injectable nanosuspension.¹⁴ Depot-formulated CAB was studied in a dose-escalation manner as both intramuscular and subcutaneous injections given monthly or quarterly.¹⁵ Rilpivirine LA injection is also a nanosuspension formulation.¹⁶ The Long-Acting Antiretroviral Treatment Enabling (LATTE) trial was a phase 2b, randomized, parallel- group study in treatment-naive adult patients with HIV-1 infection treated with oral CAB plus dual NRTIs (abacavir/lamivudine or tenofovir/ emtricitabine) as induction therapy, followed by oral CAB plus RPV maintenance therapy.¹⁷ The comparator group was efavirenz plus the dual NRTI backbone. Viral suppression was comparable in the efavirenz arm during both phases, with a numerically higher response rate and shorter time to viral suppression with CAB. Subsequently, in the randomized, open-label, noninferiority LATTE-2 trial, LA intramuscular CAB plus RPV, given in 4- or 8-week intervals ( following a 20-week oral induction period) was compared with oral CAB plus abacavir/lamivudine in HIV-1 positive adults to maintain viral suppression.¹⁸ Pre-specified efficacy criteria were met as virologic suppression was achieved in 94% of the 4-week group and 95% of the 8-week group, compared with 91% of the oral treatment group at 32 weeks, and remained so through 96 weeks. Mild to moderate injection-site pain was the most common adverse event (AE), which lasted for a median duration of 3 days. No serious AEs were considered to be related to study treatment. The authors concluded that LA CAB plus RPV offers high efficacy and acceptable safety for maintenance therapy in virologically suppressed patients living with HIV, thereby supporting advancement to future randomized controlled-trials.

For patients who wish to avoid the burden or stigma of taking daily oral ARVs or for those who struggle with the responsibility, LA injectables may be preferable.¹⁹ However, there are downsides to consider. In patients with a well-controlled viral load who may only require twice-annual office visits, the need for more frequent visits for drug administration may pose a barrier to adherence. Although AEs were generally mild with CAB plus RPV, any AE may be compounded by the fact that the offending agent has a long half-life and cannot be rapidly eliminated. Moreover, resistance is concerning if the agents are discontinued due to declining drug levels. At least 1 patient in the LATTE-2 trial developed an integrase mutation Q148R, imparting phenotypic resistance to CAB.18 This was also a concern when CAB was studied for PrEP.²⁰ Finally, the clinical trials all require oral lead-in periods that will necessitate careful management and clear understanding between patients and providers.

CONCLUSION

Recent advances in ART simplification, including the approval of the first 2-drug HIV maintenance therapy and early success of LA parenteral ARVs hold potential to significantly increase the likelihood of sustained success for patients receiving treatment for HIV. The Joint United Nations Programme on HIV/AIDS has set forth a goal for 2020: to have 90% of people living with HIV know their diagnosis, to have 90% of that group on ART, and to have 90% of those on treatment be virally suppressed (90-90-90).^21,22 These new treatment strategies could potentially have a significant impact on reaching the goal of 90-90-90.

Dr. Bailey is an assistant professor at the Notre Dame of Maryland University School of Pharmacy in Baltimore, Maryland, and a clinical specialist in infectious diseases/internal medicine at the University of Maryland Medical Center (UMMC). She earned a PharmD at the University of Maryland School of Pharmacy (UMPharm) and completed 2 years of postgraduate residency training at UMMC/UMPharm. She is an active member of SIDP.

Dr. Banoub is a clinical specialist in infectious diseases at the University of Maryland Medical Center (UMMC) in Baltimore, Maryland. She earned a PharmD at the University of North Carolina at Chapel Hill School of Pharmacy and completed her first year of residency training at the Johns Hopkins Hospital and second year infectious diseases specialty residency at Wake Forest Baptist Health. She is an active member of SIDP.

Dr. Patel is an assistant professor at the University of Maryland School of Medicine (UMMC) in Baltimore, Maryland. He earned an MD at Virginia Commonwealth University in Richmond, Virginia, and he completed internal medicine and pediatric residency training as well as infectious diseases fellowship training at UMMC.

References:

1. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Department of Health and Human Services website. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed December 16, 2017.
2. Baril JG, Angel JB, Gill MJ, et al. Dual therapy treatment strategies for the management of patients infected with HIV: a systematic review of current evidence in ARV-naive or ARV-experienced, virologically suppressed patients. PLoS One. 2016;11(2):e0148231. doi: 10.1371/journal.pone.0148231.
3. FDA approves first two-drug regimen for certain patients with HIV [news release]. Silver Spring, MD: FDA; November 21, 2017. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm586305.htm. Accessed December 12, 2017.
4. Juluca [package insert]. Research Triangle Park, NC: ViiV Healthcare; 2017.
5. Ganter P, Cuzin L, Allavena C, et al; Dat’AIDS study group. Efficacy and safety of dolutegravir and rilprivirine dual therapy as a simplification strategy: a cohort study. HIV Med. 2017;89(9):704-708. doi: 10.1111/hiv.12506.
6. Suzuki T, Hara N, Osa M, et al. Efficacy of switching to dolutegravir plus rilpivirine, the small-tablet regimen, in patients with dysphagia: two case reports. J Pharm Health Care Sci. 2017;3:23. doi: 10.1186/s40780-017-0093-8.
7. Llibre JM, Hung C-C, Brinson C, et al. Phase III SWORD 1 & 2: Switch to DTG + RPV maintains virologic suppression through 48 weeks. Oral abstract presented at: Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle, WA.
8. Wijting I, Rokx C, Boucher C, et al. Dolutegravir as maintenance monotherapy for HIV-1: a randomized clinical trial. Poster presented at: Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle, WA.
9. Joly V, Burdet C, Landman R, et al. Promising results of dolutegravir + lamivudine maintenance in ANRS 167 LAMIDOL trial. Poster presented at: Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle, WA.
10. Williams J, Sayles HR, Meza JL, et al. Long-acting parenteral nanoformulated antiretroviral therapy: interest and attitudes of HIV-infected patients. Nanomedicine (Lond). 2013;8(11):1807-1813. doi: 10.2217/nnm.12.214.
11. Rajoli RKR, Back DJ, Rannard S, et al. Physiologically based pharmacokinetic modelling to inform development of intramuscular long-acting nanoformulations for HIV. Clin Pharmacokinet. 2015;54(6):639-650. doi: 10.1007/s40262-014-0227-1.
12. Ford SL, Gould E, Chen S, et al. Lack of pharmacokinetic interaction between rilpivirine and integrase inhibitors dolutegravir and GSK1265744. Antimicrob Agents Chemother. 2013;57(11):5472-5477. doi: 10.1128/AAC.01235-13.
13. Spreen WR, Margolis DA, Pottage JC. Long-acting injectable antiretrovirals for HIV treatment and prevention. Curr Opin HIV AIDS. 2013;8(6):565-571. doi: 10.1097/COH.0000000000000002.
14. Spreen W, Ford SL, Chen S, et al. GSK1265744 pharmacokinetics in plasma and issue after single=dose long-acting injectable administration in healthy subjects. J Acquir Immune Defic Syndr. 2014;67(5):481-486. doi: 10.1097/QAI.0000000000000301.
15. Trezza C, Ford SL, Spreen W, Pan R, Piscitelli S. Formulation and pharmacology of long-acting cabotegravir. Curr Opin HIV AIDS. 2015;10(4):239-245. doi: 10.1097/COH.0000000000000168.
16. Baert L, van’t Kleester G, Dries W, et al. Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur J Pharm Biopharm. 2009;72(3):502-508. doi: 10.1016/j.ejpb.2009.03.006.
17. Margolis DA, Brinson CC, Smith GHR, et al; LAI16482 Study Team. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015; 15(10):1145-1155. doi: 10.1016/S1473-3099(15)00152-8.
18. Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017; 390(10101):1499-1510. doi: 10.1016/S0140-6736(17)31917-7.
19. Nyaku AN, Kelly SG, Taiwo BO. Long-acting antiretrovirals: where are we now? Curr HIV/AIDS Rep. 2017;14(2):63-71. doi: 10.1007/s11904-017-0353-0.
20. Markowitz M, Frank I, Grant RM, et al. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. Lancet HIV. 2017;4(8):e331-e340. doi: 10.1016/S2352-3018(17)30068-1.
21. Joint United Nations Programme on HIV/AIDS. 90-90-90: an ambitious treatment target to help end the AIDS epidemic. UNAIDS website. unaids.org/sites/default/files/media_asset/90-90-90_en_0.pdf. Published October 2014. Accessed December 15, 2017.
22. Granich R, Williams B, Montaner J, Zuniga JM. 90-90-90 and ending AIDS: necessary and feasible. Lancet. 2017; 390(10092):341-343. doi: 10.1016/S0140-6736(17)31872-X.