April 11, 2018
Current U.S. HIV Treatment Guidelines state that people living with HIV (PLWH) should be offered treatment; however, it is estimated that ~50% are not engaged in care and virologically suppressed.1,2 Some barriers to virologic suppression include daily oral dosing, comorbidities, adverse effects, and drug-drug interactions. Novel antiretroviral therapy (ART) options are necessary to minimize these barriers and adequately maintain or achieve virologic suppression. The ART pipeline includes new medications in existing drug classes as well as medications with novel mechanisms of action.
MK-8591 (EFdA), has a novel 3'-hydroxyl moiety that allows for a higher affinity to reverse transcriptase. EFdAmonophosphate prevents DNA synthesis by inhibition of reverse transcriptase translocation.3 The active anabolite of MK-8591 was found to have a longer half-life in human peripheral blood mononuclear cells compared to other NRTIs, allowing for extended interval dosing. In an open-label study, ART-naive patients (n=6) were given one dose of MK-8591 10 mg. The half-life of the anabolite was 128 hours which resulted in a 1.78 log10 drop in HIV-1 RNA.4 MK-8591 appears to maintain its efficacy in the presence of the E138K and M184V mutations.5 A recent dosing study evaluated 0.25 mg, 0.75 mg and 5 mg in 12 healthy adults and found that MK-8591 levels were above the target concentration for efficacy among all dosing strategies and remained elevated up to 30 days after treatment cessation.6 MK-8591 is being evaluated in a Phase 2 trial with doravirine (DOR) and lamivudine (3TC) in ART-naive PLWH to determine appropriate dosing.7
Doravirine (DOR) is being studied in a non-inferiority study for ART-naive patients. Patients were randomized to oral DOR 100 mg daily or darunavir 800 mg with ritonavir 100 mg daily (DRV/r) for 48 weeks plus either tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or abacavir (ABC)/3TC. DOR (n=383) was found to be noninferior to DRV/r (n=383) with 83.8% and 79.9%, achieving virologic suppression, respectively.8 In patients with a baseline HIV-1 RNA of >100,000 copies/ml, 81% and 76.4% achieved virologic suppression, in the DOR and DRV/r group, respectively. In patients with a baseline HIV-1 RNA <100,000 copies/ml, 90% of the DOR group achieved virologic suppression. In a study comparing DOR (n=66) to efavirenz (EFV) (n=66) with TDF/FTC at 48 weeks, 77.8% and 78.7% achieved virologic suppression, respectively.9 Both studies found DOR to have a favorable lipid profile and was overall well-tolerated compared to DRV/r and EFV; however, neuropsychiatric symptoms and nausea did occur.8,9 A New Drug Application was submitted for DOR with other agents in addition to a fixed-dose combination tablet of DOR/TDF/FTC. A response is anticipated in October 2018.10
Elsufavirine is an oral NNRTI, which was recently approved in Russia for the treatment of HIV in combination with other antiretrovirals.11 Like other available NNRTIs, elsufavirine has a long plasma half-life of about 8 days, allowing for once daily dosing. Safety and efficacy of elsufavirine 20 mg was compared to EFV 600 mg plus a TDF/FTC backbone in 120 ART-naive patients.12 Median baseline viral load and CD4 T-lymphocyte count in the elsufavirine and EFV groups were 50,000 copies/ml and 63,000 copies/ml; and 349 cells/mm3 and 379 cells/mm3, respectively. After 48 weeks, 81% and 73.7% of participants achieved a HIV-1 RNA < 400 copies/ml in the elsufavirine and EFV groups, respectively. Although efficacy rates were similar, there were significantly more patients who experienced adverse effects in the EFV versus elsufavirine arm, 77.6% vs. 36.7%. Common drug associated adverse effects in the elsufavirine versus EFV arm were headache (15% versus 24%), dizziness (6.7% versus 26.7%), and sleep disorders (5% versus 20.7%). Different formulations including sustained release oral, once weekly oral, and long acting parenteral forms are in development and being studied outside the U.S. for the treatment and prevention of HIV.11
Albuvirtide has a similar mechanism of action to enfuvirtide. It is being developed as a long-acting agent in ART-experienced patients who have failed first and second line therapies.13,14 Albuvirtide has a longer half-life (11 days) compared to enfuvirtide due to its ability to conjugate to serum albumin. This allows for weekly intravenous administration.14 It demonstrated potent antiviral activity with twice-daily oral lopinavir/ritonavir (LPV/r) in ART-naive (n=20) and experienced (n=92) Chinese adults with HIV.15,16 Interim results in ART-experienced patients reported albuvirtide plus LPV/r was non-inferior to LPV/r + TDF + 3TC. The most common adverse effects reported in the albuvirtide arm were diarrhea, headache, and dizziness. High cholesterol and triglycerides were also reported more often in the albuvirtide arm. Albuvirtide may offer another option for patients who cannot tolerate twice-daily subcutaneous enfuvirtide. Albuvirtide is currently in Phase 3 studies and will also begin studies with a broad spectrum HIV neutralizing antibody.17
Cenicriviroc is an oral CCR5/CCR2 antagonist which inhibits viral entry into host cells.18 Its activity against CCR2 suggests that it could have anti-inflammatory effects in patients with chronic immune activation and in fact has been studied for non-alcoholic steatohepatitis (NASH) in both PLWH and patients without HIV.19,20 CVC with TDF/FTC was compared to EFV/FTC/TDF in a 48-week trial of ART-naive patients with R5 tropic HIV-1.21 Participants (n=143) were mostly Black or White men. Median baseline HIV-1 RNA and CD4 T-lymphocyte count were 4.5 log10 copies/ml and 385 cells/mm3, respectively. The 48-week results reported 68% and 50% achieved virologic suppression in the CVC 100 mg and EFV groups, respectively (p>0.05). No significant differences in virologic suppression rates were observed when analyzed by baseline viral load stratification (22
ABX-464 halts HIV replication by inhibiting Rev activity, an HIV protein needed to make complete HIV RNA strands.23,24 It was evaluated in ART-naive adults (n=63) at varying doses for 2-3 weeks.24 A >0.5 log10 copies/ml drop from baseline was reported with ABX-464 150 mg by mouth daily. ABX-464 was evaluated for safety and efficacy in virally suppressed patients receiving ART (n=30).25 Participants were randomized to add oral ABX-464 or placebo to their current ART for 28 days after which treatment was interrupted. An overall reduction in viral DNA was reported in 53% (8/15) of ABX-464 treated patients. The average time to viral rebound was 14 and 13 days in the placebo and treatment groups, respectively. The most common adverse effects in both studies were headache and abdominal pain. A follow-up Phase 1/2 study will evaluate ABX-464 treatment for 84 days and assess the time to maximal reduction of HIV reservoirs in recently and chronically infected people with suppressed HIV-1 RNA.26
Fostemsavir is being developed for ART-experienced patients who have <2 active therapy options.13 Fostemsavir is a prodrug of temsavir (BMS-626529) and binds to the HIV gp120 protein, preventing HIV and CD4 T-lymphocyte attachment. Potent antiviral activity has been reported in an 8 day monotherapy and 48 week Phase 2b trial.27,28 Varying dosages of oral fostemsavir given with raltegravir (RAL) and TDF were compared to atazanavir/ritonavir (ATV/r) plus RAL and TDF in ART-experienced patients (n=200).28 Participants were mostly white males with a median age of 40 years. Median baseline HIV-1 RNA and CD4 T-lymphocyte counts ranged from 4.88-5.01 log10 copies/ml and 214-249 cells/mm3, respectively across all treatment groups. A higher success rate was reported in the baseline HIV-1 RNA 29
Ibalizumab (Trogarzo) was approved by the FDA in March 2018 and is the first biologic agent available for the treatment of HIV.30 It is an anti-CD4 mAb and binds to domain 2 of the CD4 receptor, blocking a conformational change necessary for viral entry.31 Safety and efficacy were studied in a 24 week Phase 3 trial of ART-experienced patients (n=40).31,32 These participants were infected on average for 21 years and about 30% of them had been treated with >10 antiretrovirals. Mean baseline HIV-1 RNA and CD4 T-lymphocyte count were 5 log10 copies/ml and 161 cells/mm3 (50% 3), respectively. An intravenous loading dose (2000 mg) of ibalizumab was given in the first week, then biweekly (800 mg) for 24 weeks. An optimized background regimen (OBR) with at least one active agent was initiated on study day 14. About 40% of patients required an investigational agent (fostemsavir) as part of their OBR and close to 50% of the population was resistant to >3 antiretroviral classes. At 24 weeks, the mean reduction in viral load was 1.6 log10 copies/ml and 43% of participants achieved virologic suppression. After 24 weeks, participants were allowed to continue ibalizumab with an OBR for up to 48 weeks (n=27). All 15 participants with suppressed plasma HIV RNA at 24 weeks maintained through week 48.33 Commonly reported adverse effects were diarrhea, dizziness, nausea, and rash. Infusion related adverse effects were not reported. Ibalizumab offers a viable option in patients with multi-drug resistant HIV who have little to no other options.
PRO-140 targets CCR5 and is being investigated as a standalone long-acting maintenance drug in virologically suppressed patients.34,25 Patients (n=42) with R5 tropic HIV-1 on a stable regimen with HIV-1 RNA 36 An update of 16 patients found that 13/16 (81%) and 10/16 (62.5%) maintained a HIV-1 RNA 37 Serious adverse effects were not reported. Injection site reactions were mild. PRO-140 is also being studied in heavily ART-experienced patients on an OBR in which participants are being administered a single SC dose of PRO-140 or placebo in addition to their existing failing regimen for 1 week then continued on weekly PRO-140 with an OBR for 24 weeks.38
UB-421 binds to domain 1 of the CD4 receptor and is being developed in Taiwan.39 UB-421 monotherapy was evaluated in 29 virologically suppressed adults who received 8 total UB-421 infusions weekly (8 weeks) or biweekly (16 weeks) after ART interruption.39 Twenty seven of the 29 participants who completed the study did not experience viral rebound during the monotherapy period. The most common treatment related adverse effect was skin rash. This agent is projected to be investigated in Phase 3 trials.13
A functional cure for HIV is limited by the ability of HIV to survive in latent reservoirs. Many LRAs are currently being studied as adjuvant therapy with a therapeutic vaccine in Phase 1/2 studies as part of a "kick and kill" strategy. This strategy "kicks" latent cells into an active state and "kills" the cell using immune response. Studies have described the utility of LRAs to minimize HIV reservoirs by promotion of latent cell activation; however, these data have not shown a significant decline in HIV reservoir cells.40 Histone deacetylation inhibitors and toll-like receptor agonists are two types of LRAs that are being evaluated.
Toll-like receptors are used to activate an immune response during an infection. Many TLR agonists have been found to activate latent HIV cells. Currently poly-ICLC (TLR3), vesatolimod (GS-9620/TRL7), and lefitolimod (TLR9) have all been studied in Phase 1/2 trials and have shown positive results in activating latent HIV cells.41-43
Romidepsin was most recently studied with a therapeutic vaccine that resulted in 5 out of 13 participants being able to remain off ART and maintain an HIV RNA of 44 Vorinostat is similarly being studied in combination with 2 different therapeutic vaccines.45,46 Panobinostat was determined to activate latent cells in a study with 15 participants but did not show an overall decrease in the number latently infected cells.47 Due to these results, it is now being studied with peginterferon alfa-2a to activate the immune response in patients who are virologically suppressed.48
The HIV capsid core is made up of p24 protein which undergoes assembly during maturation to form the core. GSCA1 alters the assembly and disassembly of the capsid core leading to non-infectious, defective virions. In preclinical studies, GS-CA1 has been found to have high in vitro potency compared to EFV, ATV, and dolutegravir (DTG) in addition to effective concentrations for up to 10 weeks post a single injection. GS-CA1 will likely enter Phase 1 trials in 2018.49
Novel formulations of ART stand to provide patients with an alternative to taking oral ART daily. Rilpivirine (RPV) is a FDA approved NNRTI that is currently available as a 25 mg tablet. Cabotegravir (CAB) is an investigational integrase stand inhibitor (INSTI). Both medications are being explored as long-acting agents given concomitantly for HIV treatment and prevention. Cabotegravir is also being studied as a long-acting oral tablet for HIV treatment. In the LATTE-2 study ART-naive participants underwent a 20 week induction and 96 week maintenance period.50 During induction, participants were given oral CAB 30 mg with ABC/3TC daily. At week 16, oral RPV 25 mg was added. At 20 weeks, 91% (n=282) of participants achieved virologic suppression. Patients who were virologically suppressed were then randomized to either continue oral therapy (n=56); change to CAB 400 mg with RPV 600 mg intramuscularly every 4 weeks (n=115); or to CAB 600 mg and RPV 900 mg intramuscularly every 8 weeks (n=115). At 96 weeks, rates of virologic suppression were 84%, 87% and 94% of patients in the oral, 4 week, and 8 week groups, respectively. These rates were not statistically significantly different between groups.50 Intramuscular CAB and RPV are being studied in ART-naive patients who maintained virologic suppression on ABC/3TC/DTG and in a switch study of virologically suppressed ART-experienced patients who switch to intramuscular CAB and RPV. Additional studies are underway to compare injections given every 4 or 8 weeks as well as for HIV prevention.13,51-53
After over two decades of ART, the innovation of HIV therapeutic options continues to advance. Long-acting formulations, novel targets, and biologic agents will advent a new era of HIV treatment and prevention, with the hope of making strides towards a functional cure. Effective implementation of these medications should remain a priority; ensuring barriers to the HIV care continuum are addressed.
Jomy M. George is a Pharmacokineticist in the Clinical Pharmacokinetics Research Unit and Co-Director of the Pharmacokinetics Research Fellowship at the National Institutes of Health. Dr. George's areas of research include antiretroviral associated drug interactions and pharmacokinetics. She is a primary or associate investigator on various clinical and PK protocols, involving healthy participants and patients with HIV/AIDS with and without malignancies. She also currently serves on the Department of Health and Human Services (DHHS) Adult Opportunistic Infections Guidelines.
Neha Sheth Pandit is an Associate Professor and Vice Chair for Research and Scholarship at the University of Maryland School of Pharmacy, Department of Pharmacy Practice and Science. Dr. Pandit serves as a clinical pharmacist in an HIV primary care clinic in Baltimore, MD. Her patient care activities have included HIV inpatient and outpatient care, infected individuals with comorbidities including HCV, malignancies and primary care. Her research has focused on her patient care activities including drug-drug interactions, medication adherence, as well as pharmacy education. Dr. Pandit currently serves on the Advisory Board for the Maryland AIDS Drug Assistance Program.
|Long-Acting Drugs for HIV|
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